WO2016033190A1

WO2016033190A1 - Radiotracer compounds

Info

Publication number: WO2016033190A1
Application number: PCT/US2015/046962
Authority: WO
Inventors: Zizhong Li; Stephen Krause; Michiyuki Suzuki; Takeo Sasaki
Original assignee: Eisai, Inc.
Priority date: 2014-08-27
Filing date: 2015-08-26
Publication date: 2016-03-03

Abstract

A compound represented by the formula (XXIX) or a salt thereof, as shown in FIG. 7, wherein at least one fluorine is fluorine-18, at least one carbon is carbon-11, at least one nitrogen is nitrogen-13, or at least one oxygen is oxygen-15, works as a tracer for use in Positron Emission Tomography.

Description

TITLE

RADIOTRACER COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to United States Provisional Patent Application No. 62/042,552, filed on August 27, 2014. That document is incorporated by reference herein.

BACKGROUND

Field

[0002] Embodiments may relate to radiolabeled compounds including tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine derivatives that may be suitable for use as Positron Emission Tomography (PET) radiotracers. Embodiments may also relate to methods of making those compounds.

Background

[0003] Glutamic acid is known as one of principal excitatory neurotransmitters working for adjusting advanced functions of memory, learning and the like in a central nervous system of a mammal. Glutamate receptors are roughly classified into two types, that is, ionotropic glutamate receptors (iGlu receptors) and metabotropic glutamate receptors (mGlu receptors) coupled with G protein (see Science, 258, 597-603, 1992).

[0004] The iGlu receptors are classified, on the basis of types of their agonists, into three types, that is, N-methyl-D-aspartate (NMDA) receptors, cc-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kainate receptors. On the other hand, the mGlu receptors have 8 subtypes (mGluRl to 8) and are classified, on the basis of a signaling system to be conjugated and pharmacological characteristics, into group I (mGluRl , mGluR5), group II (mGluR2, mGluR3) and group III (mGluR4, mGluR6, mGluR7 and mGluR8). The group II and group III mGluRs are expressed as an autoreceptor or a heteroreceptor mainly at the nerve terminal, so as to suppress adenylate cyclase via Gi protein and regulate a specific K⁺ or Ca²⁺ channel activity (see Trends Pharmacol. Sci., 14, 13 ( 1993)). [0005] Antagonists against group II mGluRs, among these glutamate receptors, show an action to improve the cognitive function in animal models and also show an antidepressant action and an antianxiety action, and therefore, it is suggested that group II mGluR antagonists are effective as a novel cognitive function enhancer or antidepressant (see Neuropharmacol., 46 (7), 907-917

(2004); Pharmacol. Therapeutics, 104(3), 233-244 (2004); Neuropharmacol., 66, 40-52 (2013)).

[0006] United States Patent Application No. 14/190,356, filed on February 26, 2014, and PCT International Patent Application No. PCT/JP2014/054724, filed February 26, 2014, are both incorporated by reference as if fully rewritten herein. Those applications report compounds, including tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine derivatives or pharmaceutically acceptable salts thereof. Compounds as described therein may have an antagonistic action against group II metabotropic glutamate receptors. Those applications also report pharmaceutical compositions comprising compounds reported therein.

[0007] Positron emission tomography (PET) is an important tool that among other capabilities, enables the non-invasive monitoring of the distribution and uptake of therapeutics intended to act as antagonists for receptors. Such a function of PET is reliant on the preparation of PET tracers, which are radioactive molecules that target one or more receptors of interest. For example, PET allows measuring the presence of the radioactive tracers at a receptor of interest, then monitors the replacement of the tracers at the receptors of interest following administration of a therapeutic intended to exert their biological function on the same receptors. PET may be used as an evaluator of pharmacodynamic response to a therapeutic. One can also use PET as a method for evaluating the number, distribution, and/or density of receptors of interest in a patient or tissue sample, potentially allowing diagnosis of a condition of interest. BRIEF SUMMARY

[0008] Embodiments provide radiolabeled compounds. In one embodiment, the radiolabeled compounds are tetrahydroimidazo[ l ,5-d] [l ,4]oxazepine derivatives. The compounds may be in the form of a free base or a pharmaceutically acceptable acid-addition salt. Embodiments may have high specificity for group II metabotropic glutamate receptors. Embodiments may be useful as radiolabeled tracers for PET applications. Particular embodiments may be useful as radiolabeled tracers for PET applications directed to the mGlu receptors mGluR2 and/or mGluR3.

[0009] In one embodiment a compound is represented by the following formula (XXIX), which is also referred to as "Compound (XXIX)", or a pharmaceuticall acceptable acid addition salt thereof:

wherein at least one fluorine is fluorine- 18 ( F), at least one carbon is carbon- 1 1 ( 1 1 C), at least one nitrogen is nitrogen- 13 ( 13 N), or at least one oxygen is oxygen- 15 (¹⁵0).

[0010] A further embodiment may provide a radioimaging composition comprising Compound (XXIX) wherein at least one fluorine is fluorine- 18, at least one carbon is carbon- 1 1 , at least one nitrogen is nitrogen- 13, or at least one oxygen is oxygen- 15, or a pharmaceutically acceptable acid addition salt thereof, as well as one or more pharmaceutically acceptable excipients.

[0011] A further embodiment may provide a method for radioimaging comprising administering as a PET tracer a radioimaging composition comprising Compound (XXIX), wherein at least one fluorine is fluorine- 18, at least one carbon is carbon- 1 1 , at least one nitrogen is nitrogen- 13, or at least one oxygen is oxygen- 15.

[0012] A further embodiment provides a compound represented by the following Formula (XXX):

(XXX)

[0013] A further embodiment may provide a radioimaging composition comprising the compound of Formula (XXX), which is also referred to as "Compound (XXX)." A further embodiment may provide a method for radioimaging comprising administering as a PET tracer a radioimaging composition comprising Compound (XXX).

ADVANTAGEOUS EFFECTS OF EMBODIMENTS

[0014] The compounds of the present invention represented by Formula (XXIX) or Formula (XXX), or in Table 1 below (all of which may hereinafter also be referred to as the radiolabeled tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine derivatives) or a pharmaceutically acceptable acid addition salt thereof may show useful activity as a tracer for group II metabotropic glutamate receptors. Therefore, the radiolabeled tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine derivatives or pharmaceutically acceptable acid addition salts thereof have a potential use as a tracer for use with PET imaging when developing therapies for diseases or symptoms for which the antagonistic action against group II metabotropic glutamate receptors effectively works. One example of such a disease is Alzheimer's disease. Particular embodiments may have a potential use as a tracer for the mGluR2 and mGluR3 receptors.

DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0015] FIG. 1A and FIG. IB show, respectively, top and side views of summed images from 5-90 minutes of acquisition of PET data from a single Sprague Dawley rat brain as reported in Example 1 , below. These images show a baseline following injection of Compound (XXX).

[0016] FIG. 2A and FIG. 2B show, respectively, top and side views of summed images from 5-90 minutes of acquisition of PET data from a single Sprague Dawley rat brain as reported in Example 1 , below. These images show the effect of blocking of Compound (XXX) by injection of the compound of Formula (XXXI), which is also referred to as "Compound (XXXI)."

[0017] FIG. 3A and FIG. 3B show, respectively, top and side views of summed images from 5-90 minutes of acquisition of PET data from a single common marmoset brain as reported in Example 1 , below. These images show a baseline following injection of Compound (XXX).

[0018] FIG. 4A and FIG. 4B show, respectively, top and side views of summed images from 5-90 minutes of acquisition of PET data from a single common marmoset brain as reported in Example 1 , below. These images show the effect of blocking of Compound (XXX) by injection of Compound (XXXI).

[0019] FIG. 5A and FIG. 5B show, respectively, time activity curves for Compound (XXX) for a single Sprague Dawley rat in the absence and presence of a high blocking dose of Compound (XXXI).

[0020] FIG. 6A and FIG. 6B show, respectively, time activity curves for Compound (XXX) for a single common marmoset in the absence and presence of a high blocking dose of Compound (XXXI).

[0021] FIG. 7 shows a compound of formula (XXIX).

DETAILED DESCRIPTION

[0022] Hereinafter, the meanings of signs, terms and the like used herein will be explained, and embodiments of the present invention will be described in details.

[0023] Accordingly, a compound of the present invention may have an asymmetric carbon atom in a molecule thereof and exist as an optically active substance or in a racemic mixture. Stereoisomers of compounds of the present invention may differ in their activities, such as for example, binding affinities. Compounds of the present invention may exist as crystal polymorphs, which includes single crystals or mixtures thereof, hydrates, solvate as well as anhydrate forms. Compounds of the present invention may exist as salts. These salts may exist as single crystals or mixtures thereof, and the salts may have various crystal polymorphisms.

[0024] An isotopically-labeled compound of the present invention may be prepared, for example, by using a readily available isotopically-labeled reagent instead of a nonisotopically-labeled reagent and by performing procedures disclosed in schemes and/or examples described below.

[0025] Herein, a "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, and is preferably a fluorine atom or a chlorine atom.

[0026] The radiolabeled tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine derivative of embodiments presented herein may exist in the form of a salt. Typically such salt forms are pharmaceutically acceptable acid-addition salts. Specific examples of a pharmaceutically acceptable acid addition salts may include inorganic acid salts (such as a sulfate, a nitrate, a perchlorate, a phosphate, a carbonate, a bicarbonate, a hydrofluoride, a hydrochloride, a hydrobromide and a hydroiodide), organic carboxylates (such as an acetate, an oxalate, a maleate, a tartrate, a fumarate and a citrate), organic sulfonates (such as a methanesulfonate, a trifluoromethanesulfonate, an ethanesulfonate, a benzene sulfonate, a toluene sulfonate and a camphorsulfonate), and amino acid salts (such as an aspartate and a glutamate).

[0027] In one embodiment a compound is represented by the following Formula XXIX) or a pharmaceutically acceptable acid addition salt thereof:

(XXIX)

wherein at least one fluorine is fluorine- 18, at least one carbon is carbon- 1 1 , at least one nitrogen is nitrogen- 13, or at least one oxygen is oxygen- 15.

[0028] A further embodiment provides a compound represented by the following Formula (XXX):

29] Table 1 provides further examples of compounds that may be

18 11 13 15

radiolabeled with ¹⁰F, "C, ^1JN, ^1J0 to prepare a useful PET tracer according to embodiments as presented herein. Each compound in Table 1 may be radiolabeled according to one or more of the reactions presented in Table 2.

Although not required, the compounds of Table 1 are generally believed to be potent negative allosteric modulators of mGluR2 and/or mGluR3 receptors .

Table 1

TABLE 2

30] Table 2 shows a number of reactions that may be suitable for radiolabeling intermediates to provide radiolabeled compounds as reported herein. Derivatives of 3-phenyl- l-(pyridin-4-yl)-5,6,8,9- tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine may be labeled with 1 1 C and 18 F by one or more of these radiolabeling methods. Starting from a corresponding tosylate (Scheme A) (as reported in Liu, Y., et al., Optimization of automated radiosynthesis of [ 1¹8⁰F]AV-45: a new PET imaging agent for Alzheimer's disease. Nucl Med Biol, 2010. 37(8): p. 917-25) the ¹⁸F labeled derivatives can be synthesized via nucleophilic replacement reaction with [ 18 F]fluoride under mild condition. [0031] ⁿC may be introduced to phenyl (Scheme B) (as reported in Andersen, V.L., et al., Palladium-mediated conversion of para-aminoarylboronic esters into para-aminoaryl-ⁿC-methanes. Tetrahedron Letters, 2013. 54: p. 213- 16; and in Forngren, T., L. Samuelsson, and B. Langstroem, A l lC-Methyl stannane (5-[ⁿC]methyl- l-aza-5-stannabicyclo[3.3.3]undecane) for use in palladium-mediated[^uC]C-C bond forming reactions with organohalides. / Label Compd Radiopharm, 2004. 47: p. 71 -78) or pyridinyl (Scheme C) (as reported in Kealey, S ., J. Passchier, and M. Huiban, Negishi coupling reactions as a valuable tool for [ 1 lC]methyl-arene formation; first proof of principle. Chem Commun (Camb), 2013. 49(96): p. 1 1326-8) moieties from corresponding halide (Br, or I) using [^uC]methyl iodide as radioactive starting material (Scheme E) via transition metal catalyzed cross coupling reaction.

[0032] The methoxyl phenyl moiety (Scheme D) (as reported in Kniess, T., K.

Rode, and F. Wuest, Practical experiences with the synthesis of [^UC]CH3I through gas phase iodination reaction using a TRACERlabFXC synthesis module. Appl Radiat hot, 2008. 66(4): p. 482-8) may be labeled with ^UC starting with corresponding phenol derivative and [^{l X}C] methyl iodide and for the derivatives with benzonitrile group (Scheme E), transition metal promoted nC-cyanation reaction may be utilized as labeling reaction (as reported in

Andersson, Y., M. Bergstrom, and B. Langstrom, Synthesis of ⁿC-labeled benzamide compounds as potential tracers for poly(ADP-ribose) synthetase. Appl Radiat Isot, 1994. 45(6): p. 707- 14).

[0033] A further embodiment may provide a radioimaging composition comprising at least one radiolabeled compound of Formula (XXIX), the compound of Formula (XXX), and/or at least one radiolabeled compound presented in Table 1. A further embodiment may provide a method for radioimaging using a radiolabeled compound or combination of radiolabeled compounds reported herein.

[0034] Next, a method for producing a compound in Table 1 or a pharmaceutically acceptable acid addition salt thereof will be described, where "compound (I)" is used to denote a genus in which compounds presented in Table 1 may be found.

Scheme 1

[0035] The compound (I) (wherein R, R_{1 ;} R₂, R₃ and R₄ represent substituents as shown in Table 1) can be prepared in accordance with Scheme 1 by, for example, the Suzuki-Miyaura reaction of a compound (II) with a compound (III). The Suzuki-Miyaura reaction can be performed by heating the compound (II) and the compound (III) in a solvent in the presence of, for example, a palladium catalyst and a base, with a phosphorus ligand added if necessary. As the palladium catalyst, for example, tetrakis(triphenylphosphine)palladium (0), palladium (II) acetate, Pd₂DBA₃ or (A-taPhos)₂PdCl₂ can be used. As the base, for example, potassium phosphate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate or cesium carbonate can be used. Besides, as the phosphorus ligand, for example, triphenylphosphine, butyl di( l- adamantyl)phosphine or 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl can be used. The solvent used in the reaction is not especially limited as long as it is an inert solvent, and for example, THF, DME, DMF, 1 ,4-dioxane, water or a mixed solvent of these can be used. The reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution, and heating by microwaves can be employed as occasion demands.

[0036] When R₄ is, for example, a hydroxymethyl group, the compound can be also produced from a compound in which R₄ is methyl by oxidation with mCPBA or the like, rearrangement reaction with acetic anhydride or the like, and alkaline hydrolysis .

[0037] When R₂ is, for example, a hydroxymethyl group, the compound can be also produced by deprotecting a corresponding compound in which a hydroxymethyl group is protected by MOM or the like.

[0038] When Ri or R₂ is, for example, an alkoxy group, the compound can be also produced by alkylating a compound, which is obtained by deprotecting a corresponding alcohol compound protected by MOM, benzyl, methyl or the like, with alkyl bromide, alkyl iodide, alkyl triflate or the like, in a solvent such as DMF or THF in the presence of a base such as potassium carbonate or cesium carbonate. This reaction is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.

[0039] When R₄ or R₂ is, for example, a fluoromethyl group, the compound can be produced by fluorination of a hydroxymethyl group with DAST, BAST or the like.

Scheme 2

[0040] The compound (II) (wherein R, Ri and R₂ represent the same as defined above) can be prepared in accordance with Scheme 2 by, for example, ester hydrolysis of a compound (IV) and decarboxylative bromination of a resulting compound (V). A solvent used in the ester hydrolysis of the compound (IV) is not especially limited as long as it is an inert solvent, and for example, methanol, ethanol, THF or a hydrous solvent thereof can be used. Besides, as a base, for example, sodium hydroxide or potassium hydroxide can be used. This reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution. A solvent used in the decarboxylative bromination of the compound (V) is not especially limited, and for example, DMF, ethanol or a mixed solvent of DMF and ethanol can be used. Furthermore, a bromine source can be, for example, NBS . If potassium carbonate or the like is used as the base, the reaction is accelerated, and the reaction is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.

[0041] When Ri or R₂ is, for example, an alkoxy group, the compound can be also produced by alkylating a compound, which is obtained by deprotecting a corresponding alcohol compound protected by MOM, benzyl, methyl or the like, with alkyl bromide, alkyl iodide, alkyl triflate or the like in a solvent such as DMF or THF in the presence of a base such as potassium carbonate or cesium carbonate. This reaction is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.

Scheme 3

[0042] The compound (IV) (wherein R, Ri and R₂ represent the same as defined above) can be prepared in accordance with Scheme 3 by, for example, condensing a compound (VI) with a compound (VII) and treating a resulting compound (VIII) with a base. A solvent used in the condensation of the compounds (VI) and (VII) is not especially limited as long as it is an inert solvent, and for example, toluene, THF, DME or a mixed solvent of these can be used. The reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution, and heating with microwaves can be employed as occasion demands. A solvent used in the treatment of the compound (VIII) with a base is not especially limited as long as it is an inert solvent, and for example, methanol can be used. The base can be, for example, sodium methoxide. The reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution, and heating with microwaves can be employed as occasion demands. When Ri or R₂ is, for example, an alkoxy group, the compound can be also produced by alkylating a compound, which is obtained by deprotecting a corresponding alcohol compound protected by MOM, benzyl, methyl or the like, with alkyl bromide, alkyl iodide, alkyl triflate or the like in a solvent such as DMF or THF in the presence of a base such as potassium carbonate or cesium carbonate. This reaction is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.

Scheme 4

(IX) (X) (XII) (VI)

43] The compound (VI) (wherein Ri and R₂ represent the same as defined above) can be prepared in accordance with Scheme 4 by, for example, acid chloridization of a compound (IX), amidation of a resulting compound (X) and a compound (XI) under basic conditions, and cyclization of a resulting compound (XII). A solvent used in the acid chloridization of the compound (IX) is not especially limited as long as it is an inert solvent, and for example, toluene or DCM can be used. Furthermore, for example, oxalyl chloride or thionyl chloride can be used for the reaction, and the reaction is accelerated by addition of DMF. The reaction is accelerated by heating, but is generally performed at a temperature ranging from an ice cooling temperature to the reflux temperature of the solution. A solvent used in the amidation of the compounds (X) and (XI) is not especially limited as long as it is an inert solvent, and for example, toluene, THF, DCM, water or a mixed solvent of these can be used. Furthermore, as a base, for example, sodium hydroxide or potassium hydroxide can be used. This reaction is generally performed at a temperature ranging from an ice cooling temperature to the reflux temperature of the solution. A solvent used in the cyclization of the compound (XII) is not especially limited as long as it is an inert solvent, and for example, toluene or THF can be used. Besides, methyl chloroformate, isopropyl chloroformate, DCC or the like can be used for the cyclization. This reaction is generally performed at a temperature ranging from -78°C to the reflux temperature of the solution.

Scheme 5

44] The compound (IV) (wherein R, R and R₂ represent the same as defined above) can be prepared also in accordance with Scheme 5 by, for example, the Suzuki-Miyaura reaction of a compound (XIII) (wherein X is halogen) and a compound (XIV). The Suzuki-Miyaura reaction can be performed by heating the compound (XIII) and the compound (XIV) in a solvent in the presence of, for example, a palladium catalyst and a base, with a phosphorus ligand added if necessary. As the palladium catalyst, for example, tetrakis(triphenylphosphine)palladium (0), palladium (II) acetate, Pd₂DBA₃ or (A-taPhos)₂PdCl₂ can be used. As the base, for example, potassium phosphate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate or cesium carbonate can be used. Besides, as the phosphorus ligand, for example, triphenylphosphine, butyl di( l- adamantyl)phosphine or 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl can be used. The solvent used in the reaction is not especially limited as long as it is an inert solvent, and for example, THF, DME, DMF, 1 ,4-dioxane or benzene can be used. The reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution, and heating by microwaves can be employed as occasion demands.

Scheme 6

(VII) (XVI) (XVII) (XIII)

45] The compound (XIII) (wherein R is the same as defined above and X is halogen) can be prepared in accordance with Scheme 6 by, for example, condensation of the compound (VII) with a compound (XV), a Hofmann rearrangement reaction of a resulting compound (XVI), and halogenation of a resulting compound (XVII). A solvent used in the condensation of the compounds (VII) and (XV) is not especially limited as long as it is an inert solvent, and for example, toluene, THF, DMF, DME or a mixed solvent of these can be used. The reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution, and heating with microwaves can be employed as occasion demands. A solvent used in the rearrangement reaction of the compound (XVI) is not especially limited as long as it is an inert solvent, and for example, toluene, THF, DME or a mixed solvent of these can be used. Furthermore, iodobenzene diacetate or the like can be used in the reaction. The reaction is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution. A solvent used in the halogenation of the compound (XVII) is not especially limited as long as it is an inert solvent, and for example, toluene can be used. Furthermore, phosphorus oxychloride or phosphorus oxybromide can be used in the reaction. The reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.

Scheme 7

(XXII) (VII)

46] The compound (VII) (wherein R is the same as defined above) can be prepared in accordance with Scheme 7 by, for example, four steps of a 1 ,4- addition reaction of a compound (XVIII) and a compound (XIX), alcoholysis of a resulting compound (XX) under acidic conditions, cyclization of a resulting compound (XXI) under basic conditions, and O-alkylation of a resulting compound (XXII). In the 1 ,4-addition reaction of the compound (XVIII), the compound(XIX) can be used as a solvent. As a base, DBU, TEA, DIPEA or the like can be used. This reaction is generally performed at a temperature ranging from an ice cooling temperature to the reflux temperature of the solution. A solvent used in the alcoholysis of the compound (XX) is not especially limited as long as it is an inert solvent, and for example, 1 ,4-dioxane can be used. As an acid, hydrogen chloride or the like can be used. This reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution. A solvent used in the cyclization of the compound (XXI) is not especially limited as long as it is an inert solvent, and for example, methanol or the like can be used. As a base, DBU, TEA, potassium carbonate or cesium carbonate can be used. This reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution. A solvent used in the O-alkylation of the compound (XXII) is not especially limited as long as it is an inert solvent, and for example, DCM or toluene can be used. As an alkylating agent, trimethyloxonium tetrafluoroborate, dimethyl sulfate or the like can be used. This reaction is generally performed at a temperature ranging from an ice cooling temperature to the reflux temperature of the solution.

Scheme 8

(xxvii) ( ii)

47] The compound (XXII) (wherein R is the same as defined above) can also be prepared in accordance with Scheme 8 by, for example, four steps of dehydrative condensation of a compound (XXIII) with a compound (XXIV), cyclization of a resulting compound (XXV) performed under acidic conditions, hydrogenation of a resulting compound (XXVI), and deprotection of a resulting compound (XXVII). A solvent used in the dehydrative condensation of the compound (XXIII) with the compound (XXIV) is not especially limited as long as it is an inert solvent, and for example, THF, DMF or DCM can be used. Besides, a condensation agent can be DCC, EDC, HOBt, HATU, HBTU or a combination of any of these. Furthermore, DIPEA, TEA or the like can be used as an additive in the reaction. This reaction is generally performed at a temperature ranging from an ice cooling temperature to the reflux temperature of the solution. A solvent used in the cyclization of the compound (XXV) is not especially limited as long as it is an inert solvent, and for example, THF, acetonitrile, toluene or xylene can be used. Besides, an acid can be, for example, PTS or PPTS . The reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution. A solvent used in the hydrogenation of the compound (XXVI) is not especially limited as long as it is an inert solvent, and for example, methanol, ethanol or THF can be used. As a catalyst, palladium/carbon, palladium hydroxide/carbon, platinum oxide or the like can be used. This reaction is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution. The deprotection of the compound (XXVII) can be performed, for example, in a solvent such as TFA. As an additive, for example, a scavenger such as a triethyl silane can be used. This reaction is accelerated by heating, but is generally performed at a temperature ranging from room temperature to the reflux temperature of the solution.

[0048] The compound (I) thus obtained can be prepared into a pharmaceutically acceptable salt by a conventional method as occasion demands. The preparation method can be an appropriate combination of, for example, methods conventionally employed in the field of synthetic organic chemistry. A specific example of the method includes neutralization titration of a solution of the free form of the present compound with an acid solution. Furthermore, the compound (I) of the present invention can be changed into a solvate by a known solvate forming reaction as occasion demands.

[0049] The compound (I) can also be provided with a radiolabel by reaction as shown in Table 2.

[0050] Representative examples of the method for producing the compound (I) have been described so far, and material compounds and various reagents used in the production method for the compound (I) may be in the form of a salt or a hydrate, and are different depending upon starting materials, solvents to be used and the like, and hence are not especially limited as long as the reactions are not retarded. Also the solvents to be used differ depending upon the starting materials, reagents and the like, and needless to say, are not especially limited as long as they do not retard the reactions and they dissolve starting materials to some extent. When the compound (I) is obtained in the form of a free form, it can be changed, by a conventional method, into the form of a salt that can be formed by the compound (I). Similarly, when the compound (I) is obtained in the form of a salt of the compound (I), it can be changed, by a conventional method, into a free form of the compound (I). Furthermore, various isomers (such as a geometric isomer, an optical isomer based on asymmetric carbon, or stereoisomers) obtained as the compound (I) can be purified and isolated by general separation means such as recrystallization, a diastereomeric salt formation method, enzymatic resolution, and various types of chromatography (including thin layer chromatography, column chromatography and gas chromatography).

[0051] The radiolabeled tetrahydroimidazo[ l ,5-d] [l ,4]oxazepine derivatives of the present invention or a pharmaceutically acceptable acid addition salt thereof may be useful as tracers for PET. Accordingly, they may be useful in studies directed to therapeutic agents for diseases in which the antagonistic action against the group II metabotropic glutamate receptors effectively works. Examples of a disease in which the antagonistic action against the group II metabotropic glutamate receptors effectively works includes Alzheimer's disease.

[0052] For particular diagnostic purposes an embodiment as reported herein may be administered orally, intravenously, or by any other method deemed suitable to the skilled technician. For producing an oral solid formulation, an excipient, a binder, a disintegrator, a lubricant, a colorant and the like can be added, if necessary, to the radiolabeled tetrahydroimidazo[ l ,5- d] [ l ,4]oxazepine derivative of the present invention or a pharmaceutically acceptable acid addition salt thereof, and the resulting mixture can be prepared by a conventional method into tablets, granules, powders or capsules. Furthermore, the tablets, granules, powders or capsules can be coated with a film if necessary.

[0053] Non-limiting examples of the excipient include lactose, corn starch and crystalline cellulose, non-limiting examples of the binder include hydroxypropyl cellulose and hydroxypropylmethyl cellulose, non-limiting examples of the disintegrator include carboxymethylcellulose calcium and croscarmellose sodium, non-limiting examples of the lubricant include magnesium stearate and calcium stearate, a non-limiting example of the colorant includes titanium oxide, and non-limiting examples of a film-coating agent include hydroxypropyl cellulose, hydroxypropylmethyl cellulose and methyl cellulose.

[0054] A solid formulation such as a tablet, a capsule, a granule or a powder may contain a radiolabeled tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine derivative reported herein, a pharmaceutically acceptable salt thereof, or a solvate thereof in a content of generally 0.001 to 99.5% by weight, preferably 0.001 to 90% by weight, and the like.

[0055] For producing an injection formulation (for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration or the like), a pH adjuster, a buffer, a suspending agent, a solubilizing agent, an antioxidant, a preservative (an antiseptic agent), a tonicity adjusting agent and the like may be added, if necessary, to a radiolabeled tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine derivative or a pharmaceutically acceptable acid addition salt thereof, and the resulting mixture can be prepared into an injection formulation by a conventional method.

[0056] Non-limiting examples of the pH adjuster and the buffer include organic acids, inorganic acids and/or salts thereof, non-limiting examples of the suspending agent include methyl cellulose, Polysorbate 80 and carboxymethyl cellulose sodium, non-limiting examples of the solubilizing agent include Polysorbate 80 and polyoxyethylene sorbitan monolaurate, a non-limiting example of the antioxidant includes alpha-tocopherol, non- limiting examples of the preservative include methyl paraoxybenzoate and ethyl paraoxybenzoate, and non-limiting examples of the tonicity adjusting agent include glucose, sodium chloride and mannitol.

57] Such an injection formulation may contain a tetrahydroimidazo[ l ,5- d] [ l ,4]oxazepine derivative of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof in a content of generally 0.000001 to 99.5% by weight, preferably 0.000001 to 90% by weight, and the like.

Hereinafter, embodiments will be described in detail with reference to

Examples, Production Examples, and Test Examples. However, the present invention is not limited to these examples. In addition, abbreviations used in Examples are commonly used abbreviations well known to the person skilled in the art, and some of the abbreviations will be described below.

(A-taPhos)₂PdCl₂: bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II)

Bn: benzyl

Boc: tert-butoxycarbonyl

DBU: l ,8-diazabicyclo[5.4.0]undec-7-ene

DCM: dichloromethane

DIPEA: diisopropylethylamine

DME: dimethoxyethane

DMF: N,N-dimethylformamide

n-: normal

NBS : N-bromosuccinimide

NMM: N-methylmorpholine

tert-: tertiary

TEA: triethylamine

TFA: trifluoro acetic acid

THF: tetrahydrofuran Ts: paratoluenesulfonyl

1H-NMR: proton nuclear magnetic resonance spectrometry

[0058] Chemical shifts of proton nuclear magnetic resonance spectra are recorded in the unit of δ (ppm) with respect to tetramethylsilane and coupling constants are recorded in the unit of Herz (Hz). Patterns include: s; singlet, d; doublet, t; triplet, q; quartet, br; broad, and sep; septet.

[0059] The term "room temperature" or "rt" in Examples and Production

Examples described below usually stands for a temperature in the range of about 10°C to 35°C. The symbol " " denotes % by weight, unless otherwise described.

[0060] We now present a series of product steps designed to prepare a compound of Formula (XXIX).

[0061] Production Example 1

[0062] Synthesis of (S)-2-((benzyloxy)methyl)-5-methoxy-2,3,6,7-tetrahydro- 1 ,4-oxazepine

[0063] (1) Synthesis of (R)-3-(benzyloxy)-2-hydroxypropyl 4-methylbenzene sulfonate

[0064] A boron trifluoride-ethyl ether complex (0.694 mL, 5.48 mmol) was added to a mixture of (2R)-(-)-glycidyl tosylate (25.0 g, 109 mmol), benzyl alcohol (22.7 mL, 219 mmol), and toluene (200 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with a saturated aqueous sodium bicarbonate solution (50.0 mL) twice and further with water (50.0 mL) twice. Ethanol was added to the organic layer until the suspension became clear. The solvent was evaporated under vacuum and the residue was purified with silica gel column chromatography (n-heptane/ethyl acetate) to obtain a title compound (28.0 g, 83.0 mmol).

lH-NMR(400MHz,CDC13)5(ppm):

2.40(d,J=5.5Hz, lH),2.44(s,3H),3.46-3.57(m,2H),3.96- 4.15(m,3H),4.50(s,2H),7.26-7.39(m,7H),7.75-7.82(m,2H).

[0065] (2) Synthesis of (R,E)-methyl 3-((l -(benzyloxy)-3-(tosyloxy)propan- 2-yl)oxy)acrylate

[0066] A mixture of the compound obtained in Production Example 1-( 1) (28.0 g, 83.2 mmol), methyl propiolate (15.3 mL, 183 mmol), NMM (9.15 mL, 83.2 mmol), and THF (280 mL) was stirred at room temperature overnight. The solvent was evaporated under vacuum and the residue was purified with silica gel column chromatography (n-heptane/ethyl acetate) to obtain a title compound (34.7 g, 82.5 mmol).

lH-NMR(400MHz,CDC13)5(ppm):

2.44(s,3H),3.57(dd,J=1.8,4.9Hz,2H),3.69(s,3H),4.14-4.30(m,3H),4.44- 4.55(m,2H),5.20(d,J=12.5Hz, lH),7.24-7.40(m,8H),7.75-7.78(m,2H).

[0067] (3) Synthesis of (R)-methyl 3-(( l-(benzyloxy)-3-(tosyloxy)propan-2- yl)oxy)propanoate

[0068] 10% Palladium/carbon (4.39 g, including 50% water content) was added to a solution of the compound obtained in Production Example l-(2) (34.7 g, 82.5 mmol) in ethanol (347 mL). The reaction mixture was stirred under hydrogen atmosphere for 7 hours. The insolubles were filtered off through Celite® material. The solvent was evaporated under vacuum to obtain a title compound (34.5 g, 82.0 mmol).

lH-NMR(400MHz,CDC13)5(ppm):

2.44(s,3H),2.51 (t,J=6.3Hz,2H),3.43-3.52(m,2H),3.66(s,3H),3.68- 3.72(m, lH), 3.74-3.85(m,2H),4.02-4.08(m, lH),4.1 1-

4.18(m, lH),4.46(s,2H),7.21-7.26(m,2H),7.28-7.40(m,5H),7.74-7.82(m,2H). [0069] (4) Synthesis of (S)-2-((benzyloxy)methyl)- L4-oxazepan-5-one

[0070] The compound obtained in Production Example l-(3) (22.0 g, 52.1 mmol) was dissolved in a 7 M ammonia/methanol solution (100 mL, 700 mmol). The reaction mixture was stirred in a sealed tube at 100 D C overnight. The reaction mixture was transferred into an eggplant shaped flask and DBU (24.9 mL, 167 mmol) was added. The reaction mixture was stirred at 80°C for 6 hours. The resultant was cooled to room temperature and the solvent was evaporated under vacuum. The residue was purified with silica gel column chromatography (n-heptane/ethyl acetate) to obtain a title compound (5.56 g, 23.6 mmol).

lH-NMR(400MHz,CDC13)5(ppm):

2.48-2.56(m, lH),2.91 (ddd,J=2.7, 1 1.0, 15.5Hz, 1H),3.24-3.33(m, lH), 3.35- 3.44(m,2H),3.53(dd,J=4.7,9.8Hz, lH),3.61- 3.76(m,2H),4.04(ddd,J=2.7, 5.2, 12.8Hz, lH),4.49- 4.60(m,2H),5.92(brs, lH),7.27-7.41 (m,5H).

[0071] (5) Synthesis of (S)-2-((benzyloxy)methyl)-5-methoxy-2,3,6,7- tetrahydro- 1 ,4-oxazepine

[0072] Trimethyloxonium tetrafluoroborate (3.31 g, 22.3 mmol) was added to a solution of the compound obtained in Production Example l -(4) (4.78 g, 20.3 mmol) in DCM (60.0 mL) at room temperature, and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated under vacuum to obtain a title compound (5.05 g, 20.3 mmol).

lH-NMR(400MHz,CDC13)5(ppm):

2.44(ddd, l .2,4.4, 15.5Hz, lH),2.90(ddd,J=3.1 , 1 1.6, 15.3Hz, 1H), 3.41- 3.65(m,9H),3.97(ddd,J=3.1 ,4.6, 12.2Hz, lH),4.53-4.60(m,2H),7.27-7.42(m,5H).

[0073] Example 1

[0074] Synthesis of (S)-( l-(2,6-dimethylpyridin-4-yl)-3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5, 6,8, 9-tetrahydroimidazor i,5-di r 1 ,41 oxazepin-6- yPmethanol

[0075] ( 1) Synthesis of 2-(3-methoxy-4-(trifluoromethoxy)benzamido)acetic acid

[0076] To a suspension of 3-methoxy-4-(trifluoromethoxy)benzoic acid (CAS No. 1261652-99-6, 5.67g, 24.0mmol) and DMF (0.18mL, 2.40mmol) in DCM (150mL) was added oxalyl choloride (2.47mL, 28.8mmol) at 0°C. The mixture was stirred at room temperature for lhr. The volatile was removed in reduced pressure to give corresponding acid-chloride. In an another flask, to a mixture of glycine (2.16g, 28.8mmol) and NaOH(aq) (2M, 40mL) was added the solution of former prepared acid chloride in THF(40mL) at 0°C. The mixture was stirred for 15hr at rt. The mixture was acidified with HCl(aq) (5M) at 0°C. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous MgS04. The volatile was removed in reduced pressure to give 2-(3-methoxy-4-(trifluoromethoxy)benzamido)acetic acid (7.04g, 24.0 mmol).

1H NMR(400 MHz, Methanol-d4)5 ppm 3.95 (s, 3H), 4.09 (s, 2H), 7.35 (dd, J= 8.20, 1.17Hz, 1H), 7.49 (dd, J=8.20Hz, 1.95Hz), 7.64 (d, J=1.95Hz, 1H)

[0077] (2) Synthesis of (S)-methyl 6-((benzyloxy methyl -3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5, 6,8, 9-tetrahydroimidazorL5-di r 1 ,41 oxazepine- 1 - carboxylate

[0078] To a solution of 2-(3-methoxy-4-(trifluoromethoxy)benzamido)acetic acid (4.12 g, 14.0 mmol) and NMM ( 1.62 ml, 14.7 mmol) in THF (75mL) was added methyl chloroformate (1.14 ml, 14.7 mmol) at - 10°C. The mixture was stirred for lhr at - 10°C then gradually warmed to rt over 2hr. The resultant solid (HC1 salt of amine) was removed on Celite®. The filtrate was concentrated in reduced pressure. The residue and (S)-2-((benzyloxy)methyl)- 5-methoxy-2,3,6,7-tetrahydro- l ,4-oxazepine (3.5g, 14.0 mmol, obtained in Production example l-(5)) were dissolved with Toluene (50 ml). The mixture was refluxed for 6hr. The mixture was cooled to rt and concentrated in a vacuum. The residue was dissolved with methanol (75 ml). Sodium methoxide (0.758 g, 14.0 mmol) was added to the mixture. The mixture was refluxed for 2.5hr and then cooled to rt. The mixture was partitioned between AcOEt and aqueous NH₄C1. The organic layer was washed with brine, dried over MgS0₄ and concentrated in vacuo. The residue was purified by chromatography on Si0₂ (Hep/AcOEt) to give (S)-methyl-((benzyloxy)methyl)-3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazo[ l,5-d] [ l ,4]oxazepine- l- carboxylate (4.10g, 8.10 mmol).

1H NMR(400 MHz, CDC13)5 ppm 3.02-3.18 (m, 1H), 3.43 (dd, J=9.37, 8.20Hz, 1H), 3.60-3.71 (m, 2H), 3.73-3.80 (m, 1H), 3.86 (s, 3H), 3.89-3.98 (m, 1H), 3.90 (s, 3H), 4.06-4.20 (m, 1H), 4.22-4.32 (m, 1H), 4.50 (s, 2H), 4.65 (d, J= 14.84Hz, 1H), 6.91-6.98 (m, 1H), 7.03 (d, J= 1.17Hz, 1H), 7.21 (dd, J=6.44, 2.93Hz, 2H), 7.24 (d, J= 1.95Hz, 1H), 7.31-7.35 (m, 3H) ESI-MS m/z 507 [M+H] +

[0079] (3) Synthesis of

(S)-6-((benzyloxy)methyl)- l-bromo-3-(3-methoxy-4-

(trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazorL5-di r L41oxazepine

[0080] A mixture of (S)-methyl 6-((benzyloxy)methyl)-3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine- l- carboxylate (4.10g, 8.10 mmol) and NaOH(aq) (5M, 3.24 ml, 16.2 mmol) in EtOH (35ml) was refluxed for lhr. The mixture was cooled to rt. The mixture was acidified with HCl(aq) (5M), then concentrated in a vacuum. The residue was diluted in EtOH, and insoluble salt was removed by filtration. The filtrate was concentrated in vacuo. The residue was dissolved in DMF (40ml) and EtOH (5 ml). To the stirred mixture was added K₂C0₃ (2.80 g, 20.2 mmol) and NBS (2.16 g, 12.1 mmol) at rt. The mixture was stirred for 15hr at rt. The mixture was diluted with AcOEt and brine. The layers were separated. The organic layer was washed with brine, dried over MgS0₄, filtered, and purified by chromatography on NH-Si0₂ ( Hep/AcOEt) to give (S)-6-((benzyloxy)methyl)- l-bromo-3-(3-methoxy-4-

(trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazo[ l,5-d] [ l ,4]oxazepine (3.2g, 6.07 mmol).

1H NMR(400 MHz, CDC13)5 ppm 2.95-3.14 (m, 2H) 3.43 (dd, J=9.57, 8.01Hz, 1H) 3.57-3.67 (m, 2H) 3.71-3.81 (m, 1H) 3.84-3.94 (m, 1H) 3.86 (s, 3H) 4.18- 4.31 (m, 1H) 4.51 (s, 2H) 4.67 (d, J=14.45Hz, 1H) 6.93 (dd, J=8.40, 2.15Hz, 1H) 7.01 -7.09 (m, 1H) 7.19-7.25 (m, 3H) 7.29-7.36 (m, 3H)

ESI-MS m/z 527 [M+H] +

[0081] (4) Synthesis of (S)-6-((benzyloxy)methyl)- l-(2,6-dimethylpyridin-4- yl)-3-(3-methoxy-4-(trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazor L5- di ri,41oxazepine

[0082] A mixture of (S)-6-((benzyloxy)methyl)- l-bromo-3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazo[l ,5-d] [ l ,4]oxazepine (3.2g, 6.07 mmol), 2,6-dimethyl-pyridine-4-boronic acid ( 1.10 g, 7.28 mmol), (A-taPhos)₂PdCl₂ (0.43 g, 0.607 mmol) and Na₂C0₃ ( 1.61 g, 15.2 mmol) in Ethanol (60 ml) was stirred for 4hr at 80°C. The mixture was purified by chromatography on NH-Si0₂ (Hep/AcOEt) and then re-purified by chromatography on Si0₂ (Hep/AcOEt to AcOEt/MeOH) to give (S)-6- ((benzyloxy)methyl)- l-(2,6-dimethylpyridin-4-yl)-3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine (1.53g, 2.76 mmol).

IH NMR(400 MHz, CDC13)5 ppm 2.55 (s, 6H), 3.13-3.26 (m, IH), 3.38 (dd, J=16.21 , 3.71Hz, IH), 3.46 (dd, J=9.57, 8.01Hz, IH), 3.63-3.73 (m, 2H), 3.79-3.88 (m, IH), 3.86 (s, 3H), 3.95 (dd, J= 14.84, 8.59Hz, IH), 4.22-4.34 (m, IH), 4.53 (s, 2H), 4.67 (d, J=14.84Hz, IH), 6.97-7.02 (m, IH), 7.05-7.1 1 (m, IH), 7.17-7.26 (m, 5H), 7.30-7.37 (m, 3H)

ESI-MS m/z 554 [M+H] +

[0083] (5) Synthesis of (S)-( l-(2,6-dimethylpyridin-4-yl)-3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5, 6,8, 9-tetrahydroimidazorL5-di r 1 ,41 oxazepin-6- yPmethanol

[0084] A mixture of (S)-6-((benzyloxy)methyl)- l -(2,6-dimethylpyridin-4-yl)- 3-(3-methoxy-4-(trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazo[ l ,5- d] [ l ,4]oxazepine (1.53g, 2.76 mmol), 1 ,4-cyclohexadiene ( 15ml, 160mmol), 20% Pd(OH)₂-C (500mg) in MeOH ( 15 ml, 371 mmol) was stirred at 90°C. After 26hr, additional 1 ,4-cyclohexadiene ( 15ml, 160 mmol) and Pd(OH)2-C (500mg) were added to the mixture. The mixture was stirred at 90°C for 30hr. Additional 1 ,4-cyclohexadiene ( 15ml, 160 mmol) was added to the mixture. The mixture was stirred at 90°C for 20hr. Additional 1 ,4-cyclohexadiene (15ml, 160 mmol) and Pd(OH)2-C (500mg) were added to the mixture. The mixture was stirred at 90°C for 19.5hr. Additional 1 ,4-cyclohexadiene ( 15ml, 160 mmol) and Pd(OH)2-C (500mg) were added to the mixture. The mixture was stirred at 90°C for 24.5hr. Additional 1 ,4-cyclohexadiene ( 15ml, 160 mmol) and Pd(OH)2-C (500mg) were added to the mixture. The mixture was stirred at 90°C for 24hr. The reaction mixture was cooled to rt and filtered through a Celite® to remove Pd catalyst. 250ml of AcOEt was used for washing the removed catalyst. The filtrate was concentrated in vacuo and purified by chromatography on NH-Si0₂ (Hep/AcOEt to AcOEt/MeOH) to give (S)-(l -(2,6-dimethylpyridin-4-yl)-3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazo[ l,5-d] [ l ,4]oxazepin-6- yl)methanol (690 mg, 1.49 mmol).

IH NMR(400 MHz, CDC13)5 ppm 2.56 (s, 6H), 3.1 1-3.28 (m, IH), 3.41 (dd, J=16.01 , 3.91 Hz, IH), 3.58-3.77 (m, 4H), 3.94 (s, 3H), 4.03 (dd, J=14.84, 8.20Hz, IH), 4.24-4.37 (m, IH), 4.46 (d, J= 14.45Hz, IH), 7.01 (dd, J= 8.20, 1.95 Hz, IH), 7.21 (s, 2H), 7.25-7.27 (m, IH), 7.32 (dd, J=8.20, 1.17Hz, IH)

ESI-MS m/z 464 [M+H] +

[0085] Example 2 - Alternative Method for Synthesis of (S -(l-(2,6- dimethylp yridin-4-yl)-3-(3-methoxy-4-(trifluoromethoxy)phenyl)-5, 6,8,9- tetrahydroimidazor 1 ,5-dl Γ 1 ,41 oxazepin-6-yl)methanol

[0086] (1) Synthesis of (S -methyl 6-(hydroxymethyl -3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5, 6,8, 9-tetrahydroimidazori ,5-di r 1 ,41 oxazepine- 1 - carboxylate

[0087] A solution of (S)-methyl 6-((benzyloxy)methyl)-3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazo[ l,5-d] [ l ,4]oxazepine- l- carboxylate (640 mg, 1.26 mmol) in MeOH (20 ml, 494 mmol) was circulated in a H-cube® continuous-flow hydrogenation reactor in which 20% Pd(OH)₂ cartridge was attached. After circulating the solvent for 3 h under H₂ atmosphere ( 10 bar) at 60 °C, the reaction was confirmed to complete by LC- MS, and then the solvent was removed under reduced pressure. The residue was purified by NH-silica gel column chromatography (Heptane/AcOEt) to afford (S)-methyl 6-(hydroxymethyl)-3-(3-methoxy-4-

(trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazo[ l,5-d] [ l ,4]oxazepine- l- carboxylate (515 mg, 1.24 mmol).

1H NMR(400 MHz, CDC13)5 ppm 1.99-2.04 (m, 1H), 3.04-3.14 (m, 1H), 3.61-3.72 (m, 4H), 3.91 (s, 3H), 3.93 (s, 3H), 4.00-4.07 (m, 1H), 4.14-4.21 (m, 1H), 4.28-4.35 (m, 1H), 4.42-4.48 (m, 1H), 6.95-7.00 (m, 1H), 7.24-7.26 (m, 1H), 7.29-7.33 (m, 1H)

ESI-MS m/z 417 [M+H] +

[0088] (2) Synthesis of (S)-( l-bromo-3-(3-methoxy-4-

(trifluoromethoxy)phenyl)-5, 6,8, 9-tetrahydroimidazorL5-di r 1 ,41 oxazepin-6- yPmethanol

[0089] To a stirred solution of (S)-methyl 6-(hydroxymethyl)-3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazo[l ,5-d] [ l ,4]oxazepine- l- carboxylate (64 mg, 0.154 mmol) in EtOH (3 ml) was added NaOHaq (5M, 0.061 ml, 0.307 mmol) at rt. After stirring for 4 h at 45°C, to the mixture was added HCl(aq) (5M, 0.06 ml) and the generated precipitate was removed by suction (washed with EtOH). The filtrate was evaporated and the residue was dissolved in DMF (2 ml), and then K₂C0₃ (42.5 mg, 0.307 mmol) an NBS (30.1 mg, 0.169 mmol) were added to the mixture at rt. After stirring for 14 h at rt, the mixture was partitioned between H₂0 EtOAc. The separated organic layer was washed with brine. The organic layer was dried over MgS0₄, filtered off, and concentrated in vacuo. The residue was purified by NH-Si0₂ column chromatography (H/A=2) to afford (S)-(l -bromo-3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazo[ l,5-d] [ l ,4]oxazepin-6- yl)methanol (41 mg, 0.094 mmol).

IH NMR(400 MHz, CDC13)5 ppm 2.19-2.29 (m, IH) 2.97-3.06 (m, IH) 3.08- 3.16 (m, IH) 3.59-3.70 (m, 4H) 3.92 (s, 3H) 3.94-4.02 (m, IH) 4.24-4.31 (m, IH) 4.44-4.50 (m, IH) 6.92-6.97 (m, IH) 7.21 -7.23(m, IH) 7.27-7.30 (m, IH)

ESI-MS m/z 437 [M+H] +

[0090] (3) Synthesis of (S -( l-(2,6-dimethylpyridin-4-yl -3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5, 6,8, 9-tetrahydroimidazorL5-di r 1 ,41 oxazepin-6- yPmethanol

[0091] A mixture of (S)-( l-bromo-3-(3-methoxy-4-(trifluoromethoxy)phenyl)- 5,6,8,9-tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepin-6-yl)methanol ( 140 mg, .32 mmol), 2,6-dimethyl-pyridine-4-boronic acid (62.8 mg, .416 mmol), (A- taPhos)₂PdCl₂ (22.67 mg, 0.032 mmol), Na₂C0₃ (85 mg, 0.801 mmol) in EtOH (3ml, 51.4 mmol) was stirred at 80°C for 4 h under N₂ atomsphere. The mixture was cooled to rt and partitioned between AcOEt and water. The organic extracts were washed with brine, dried over anhydrous MgS0₄, filtered and concentrated in vacuo. The residue was purified by chromatography twice on Si0₂ (1 st chromatography NH-Si0₂, Hep/AcOEt→ AcOEt/MeOH, 2nd chromatography Si0₂ Hep/AcOEt to AcOEt/MeOH) to afford (S)-(l-(2,6-dimethylpyridin-4-yl)-3-(3-methoxy-4-

(trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazo[ l,5-d] [ l ,4]oxazepin-6- yl)methanol (95 mg, 0.205 mmol, 64.0 % yield)

IH NMR(500 MHz, CDC13)5 ppm 2.56 (s, 6H) 3.21 (ddd, J=16.34, 1 1.22,

2.20Hz, IH) 3.41 (dd, J=16.34, 4.15 Hz, IH) 3.65-3.79 (m, 4H) 3.94 (s, 3H) 4.03 (dd, J=14.88, 8.05Hz, IH) 4.29-4.38 (m, IH) 4.47 (d, J=14.63Hz, IH)

7.02 (dd, J= 8.29, 1.95 Hz, IH) 7.21 (s, 2H) 7.25-7.27 (m, IH) 7.32 (dd,

J=8.29, 1.17Hz, IH)

ESI-MS m/z 464 [M+H] +

[0092] Example 3 - Synthesis of (S)- l -(2,6-dimethylpyridin-4-yl)-6-(^'(^'fluoro- 18F)methyl)-3-(3-methoxy-4-(trifluoromethoxy)phenyl)-5,6,8,9- tetrahydroimidazor 1 ,5-dl Γ 1 ,41 oxazepine

[0093] ( 1) Synthesis of (S)-( l-(2,6-dimethylpyridin-4-yl)-3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazorL5-di r L41oxazepin-6- yPmethyl 4-methylbenzenesulfonate

[0094] To a stirred solution of (S)-( l-(2,6-dimethylpyridin-4-yl)-3-(3- methoxy-4-(trifluoromethoxy)phenyl)-5, 6,8,9 -tetrahydroimidazo[ 1 ,5- d] [ l ,4]oxazepin-6-yl)methanol (50 mg, 0.108 mmol) in dichloromethane ( 1 ml) was added 4-methylbenzenesulfonic anhydride (52.8 mg, 0.162 mmol) and diisopropylethylamine (56.5 ul, 0.324 mmol). The mixture was stirred at room temperature for 24 h. Additional portion of 4-methylbenzenesulfonic anhydride (52.8 mg, 0.162 mmol) was added and the mixture was stirred for 48 h. The reaction mixture become dark brown. The solvent was removed under reduced pressure, the residue was re-dissolved in dichloromethane (2 ml). The solution was loaded on a pre-packed silica gel cartridge ( 12 g), the product was eluted with a mixture of heptane and ethyl acetate ( 100/0; 70/30; 50/50; 70/30; 20/80, v/v). The fractions contained product was pooled and solvent was evaporated to give product as white foam (44 mg, 66%).

1H NMR(400 MHz, CDC13)55 ppm 2.45 (s, 3H) 2.60 (br, 6H) 3.1 1-3.28 (m, 1H) 3.38 (dd, J = 16.02, 3.91 Hz, 1H) 3.66 (t, J = 1 1.73 Hz, 1H) 3.86-3.98 (m,

3H) 3.95(s, 3H) 4.18 (dd, J = 10.16, 3.91 Hz, 1H) 4.22-4.28 (m, 1H) 4.53 (d, J = 14.01Hz, 1H) 6.98 (dd, J = 8.20, 1.95 Hz, 1H) 7.22(d J = 1.95 Hz 1H) 7.26 (s 2H) 7.29 (dd, J = 8.21 , 1.62 Hz, 1H) 7.33 (d, J = 8.83Hz, 2H) 7.72 (d, J = 8.61.2H)

ESI-MS m/z 619 [M+H] +

[0095] (2) (S)- l-(2,6-dimethylpyridin-4-yl)-6-((fluoro- 18F)methyl)-3-(3- methoxy-4-(trifluoromethoxy)phenyl)-5, 6,8,9 -tetrahydroimidazo Γ 1 ,5- di r i ,41oxazepine

[0096] [¹⁸F]Fluoride aqueous solution (0.2 to 0.5 ml, PETNET solutions Woburn, MA 01810), Tetrabutylammonium hydrogen carbonate (0.65 ml, 0.075M, ABX, Radeberg, Germany). (S)-( l-(2,6-dimethylpyridin-4-yl)-3-(3- methoxy-4-(trifluoromethoxy)phenyl)-5, 6, 8, 9 -tetrahydroimidazo [ 1 , 5- d] [ l ,4]oxazepin-6-yl)methyl 4-methylbenzenesulfonate solution in acetonitrile (0.5 ml, 4 mg/ml) were loaded on an automatic radiochemistry synthesis module (Nanotek Liquid Flow (LF) Microchemistry System, Advion Biosystem, Inc, Ithaca, NY 14850). The flow rate was set to 20 μΐ/min and reactor temperature at 160 °C; the collected reaction mixture was purified on HPLC system with a reverse phase semipreparative column. The product was eluted with a mixture of water (0.1 % Triethylamine) and acetonitrile (50:50, v/v) at a flow rate of 5 ml/min. The product peak was collected from 18 to 20 min. The HPLC solvent was the evaporated under reduced pressure; the product was re-dissolved in a mixture saline and ethanol (3 ml 90: 10 v/v). The solution was sterile filtered through 0.22 um membrane filter. The product ( 1 to 2 mCi) was delivered immediately after formulation for animal PET imaging experiments. Quality control was performed on an analytical HPLC system with a reverse phase analytical column eluted with a mixture of acetonitrile and water (40 mM NH₄OAc) (gradient from 30/70 to 100/0 in 12 min, 100/0 for 5 min). The product co-eluted at 10 min with the compound prepared according to Example 4. UV detection was performed at 254 nm. The radiochemical yield is in the range 20 to 35% (decay non-corrected); the specific activity is in the range of 0.5 to 1.0 Ci/μΜ.

[0097] Example 4- Synthesis of (S)- l -(2,6-dimethylpyridin-4-yl)-6- (fluoromethyl)-3- (3-methoxy-4-(trifluoromethoxy)phenyl)-5, 6,8,9- tetrahydroimidazor 1 ,5-dl Γ 1 ,41 oxazepine.

[0098] We now present a series of reactions, given as Production Examples 2- 5 and collectively as Example 4, to produce (S)- l-(2,6-dimethylpyridin-4-yl)- 6-(fluoromethyl)-3-(3-methoxy-4-(trifluoromethoxy)phenyl)-5,6,8,9- tetrahydroimidazo[ l ,5-d] [ l ,4]oxazepine, which is also referred to as Compound (XXIX).

[0099] Production Example 2

[0100] Synthesis of (S)-2-(fluoromethyl)-5-methoxy-2.3.6.7-tetrahydro- l ,4- oxazepine

[0101] ( 1) Synthesis of (S)- l-(benzyloxy)-3-((2,4- dimethoxybenzyl)amino)propan-2-ol

[0102] Lithium bis(trifluoromethanesulfonyl)imide (87 g, 304.5 mmol) was added to a solution of 2,4-dimethoxybenzylamine (CAS No. 20781 -20-8; 46.7 mL, 310.6 mmol) and (S)-(+)-benzyl glycidyl ether (CAS No. 16495- 13-9;

50.0 g, 304.5 mmol) in DCM (1.0 L) under water-cooling. The reaction mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture to separate the organic layer. The organic layers were dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain a crude title compound ( 119.4 g).

ESI-MS m/z 332 [M+H] +

[0103] (2) Synthesis of (S)-N-(3-(benzyloxy)-2-hvdroxypropyl)-N-(2,4- dimethoxybenzyl)-3,3-dimethoxypropanamide

[0104] EDC (88 g, 456.7 mmol) and HOBT (456.7 mmol) were added to a solution of the compound obtained in Production Example 2-(l) ( 1 19.4 g),

3.3- dimethoxypropionic acid (47.0 g, 350.1 mmol), and DIPEA ( 159 mL) in DMF (800 mL) at room temperature. The reaction mixture was stirred for 16 hours, and then ethyl acetate and a saturated aqueous sodium chloride solution were added. The organic layer was separated and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was filtered through a silica gel pad (NH silica gel + silica gel, ethyl acetate). The resultant filtrate was concentrated under reduced pressure to obtain a crude title compound ( 125.5 g).

ESI-MS m/z 470 [M+Na] +

[0105] (3) Synthesis of (S)-2-((benzyloxy)methyl)-4-(2,4-dimethoxybenzyl)-

3.4- dihydro- L4-oxazepin-5(2H)-one

[0106] A solution of the compound obtained in Production Example 2-(2) ( 125.5 g) and PPTS (35.2 g, 140.2 mmol) in xylene ( 1 L) was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to separate the organic layer. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the resultant residue was purified by column chromatography (n-heptane/ethyl acetate) to obtain a title compound (57.7 g, 150 mmol).

ESI-MS m/z 384 [M+H]+, 406 [M+Na] +

[0107] (4) Synthesis of (S)-4-(2,4-dimethoxybenzyl)-2-(hvdroxymethyl)- l ,4- oxazepan-5-one

[0108] A mixture of the compound obtained in Production Example 2-(3) (57.7 g, 150.5 mmol), 20% palladium hydroxide/carbon (6 g, including 50% water content), acetic acid (20 mL), and ethanol (600 mL) was stirred under hydrogen atmosphere at 4 to 5 MPa and 70°C for 50 hours. The reaction mixture was cooled to room temperature. The insolubles were filtered off through Celite® filter and the resultant was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (n-heptane/ethyl acetate — > ethyl acetate/methanol) to obtain a title compound (33.7 g).

1H-NMR(400MHz,CDC13) δ

(ppm): 1.83(dd,J=5.1 ,7.0Hz, lH),2.63(dd,J=5.1 , 15.2Hz, lH),2.95(ddd,J=2.7, l l .

3, 15.6Hz, lH),3.22-3.30(m,2H),3.40-

3.45(m,2H),3.51 (dd,J=8.2, 16.0Hz, lH),3.62-

3.67(m, lH),3.80(s,3H),3.81 (s,3H),4.04(ddd,J=2.3,5.1 , 12.5Hz, lH),4.36(d,J=14 .5Hz, lH),4.73(d,J=14.5Hz, lH),6.43-6.47 (m,2H),7.22(d,J=8.6Hz, lH).

ESI-MS m/z 296 [M+H]+, 318 [M+Na] +

[0109] (5) Synthesis of (S)-4-(2,4-dimethoxybenzyl)-2-(fluoromethyl)- l ,4- oxazepan-5-one

[0110] Perfluorobutanesulfonyl fluoride (45.1 mL, 251.0 mmol) is added to a solution of the compound obtained in Production Example 2-(4) (33.7 g, 1 14.1 mmol), DIPEA (49.2 mL, 285.3 mmol), and tetrabutylammonium difhiorotriphenyl silicate (73.9 g, 136.9 mmol) in THF (600 mL) at room temperature. The reaction mixture was stirred at room temperature for 64 hours. The reaction mixture was concentrated under reduced pressure. A mixed solvent of toluene/ethyl acetate (5/1 ) and a saturated aqueous sodium chloride solution were added to the resultant residue to separate the organic layer. The organic layer was further washed with a saturated aqueous sodium chloride solution twice. The organic layer was concentrated under reduced pressure and the resultant residue was purified serially by silica gel column chromatography (n-heptane/ethyl acetate) and NH silica gel column chromatography (n-heptane/ethyl acetate) to obtain a crude title compound (41 g).

¹H-NMR(400MHz,CDC13) δ

(ppm):2.62(dd,J=5.5, 15.2Hz, lH),2.96(ddd,J=2.3, 1 1.3, 15.2Hz, lH),3.35- 3.68(m,4H),3.80(s,3H),3.81 (s,3H),4.00(ddd,J=2.3,5.1 , 12.5Hz, lH),4.09- 4.36(m,2H),4.40(d,J=14.5Hz, lH),4.74(d,J=14.5Hz, lH),6.44- 6.47(m,2H),7.24(d,J=8.2Hz, lH).

ESI-MS m/z 298 [M+H] +

[0111] (6) Synthesis of (S)-2-(fluoromethyl)- l ,4-oxazepan-5-one

[0112] Triethylsilane (27.4 mL, 171.7 mmol) was added to a solution of the compound obtained in Production Example 2-(5) (41 g) in TFA (300 mL) at room temperature. The reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (n- heptane/ethyl acetate — > ethyl acetate/methanol) to obtain a title compound (15 g, 101.94 mmol).

1H-NMR(400MHz,CDC13) δ

(ppm):2.54(ddd,J=2.0,5.1 , 15.6Hz, lH),2.93(ddd,J=2.7, l 1.3, 15.6Hz, 1H), 3.23- 3.31 (m, lH),3.46(ddd,J=3.5,8.6, 15.2Hz, lH),3.66-

3.78(m,2H),4.07(ddd,J=2.7,5.1 , 12.5Hz, lH),4.24-4.53(m,2H),6.50(brs, lH). [0113] (7) Synthesis of (S)-2-(fluoromethyl)-5-methoxy-2,3,6,7-tetrahvdro- 1 ,4-oxazepine

[0114] Trimethyloxonium tetrafhioroborate ( 17.34 g, 1 17.2 mmol) was added to a solution of the compound obtained in Production Example l -(6) ( 15 g, 101.94 mmol) in DCM (400 mL) at room temperature. The reaction solution was stirred at room temperature for 14 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Chloroform was added to the mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain a title compound ( 14.9 g, 93 mmol).

1H-NMR(400MHz,CDC13) δ (ppm):2.47(ddd,J=1.2,4.3, 15.6Hz, lH),2.87- 2.96(m, lH), 3.45-3.70(m,4H),3.63(s,3H),3.98(ddd,J=3.1 ,4.3, 12.1HZ, 1H),4.30- 4.50(m,2H).

[0115] Production Example 3

[0116] Synthesis of (S)-methyl 3-chloro-6-(fiuoromethyl)-5,6,8,9- tetrah droimidazor 1 ,5-d] Γ 1 ,41 oxazepine- 1 -carboxylate

[0117] A solution of the compound obtained in Production Example 2-(7) (9.39 g, 58.3 mmol)and methyl carbamoyl acetate (CAS No. 51513-29-2; 18.3 g, 156 mmol) in THF (40 mL)/DMF (10 mL) was stirred at 90°C for 15 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The resultant residue was purified by silica gel chromatography (n-heptane/ethyl acetate— > ethyl acetate/methanol) to obtain a purified compound.

[0118] Iodobenzene diacetate (24.1 g, 74.7 mmol) was added to a solution of the purified compound in THF (100 mL)/toluene (100 mL), and the mixture was stirred at room temperature for 60 hours. A saturated aqueous sodium bicarbonate solution (60 mL) and a saturated aqueous sodium sulfite solution (60 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (n-heptane/ethyl acetate— > ethyl acetate/methanol) to obtain a further purified compound.

[0119] A mixture of the further purified compound and phosphorus oxychloride (60 mL) was stirred at 1 10°C for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (n-heptane/ethyl acetate) to obtain a title compound ( 1.77 g, 6.74 mmol).

1H-NMR(400MHz,CDC13) δ (ppm):3.02(ddd,J=2.7, 1 1.4, 16.4Hz, lH),3.58-

3.65(m, lH), 3.71 -3.80(m, lH),3.88(s,3H),3.98-4.09(m,2H),4.23- 4.28(m, lH),4.33-4.65(m,3H).

ESI-MS m/z 263 [M+H] +

[0120] Production Example 4

[0121] Synthesis of 2-(3-methoxy-4-(trifluoromethoxy)phenyl)-4, 4,5,5- tetramethyl- 1 ,3,2-dioxaborolane

[0122] Pd(dppf)C12-CH2C12 ( 171 mg, 209 μπιοΐ) was added to a solution of 4- bromo-2-methoxy- l-(trifluoromethoxy)benzene (CAS No. 672948-65- 1 ; 5.23 g, 19.7 mmol), potassium acetate (616 mg, 6.28 mmol), and bis(pinacolate)diboron ( 1.06 g, 4.19 mmol) in DMF ( 10 mL) at room temperature. The reaction mixture was stirred at 1 10°C for 2 hours and then cooled to room temperature. The reaction solution was diluted with ethyl acetate, then the resultant was washed with water five times and then with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The resultant residue was purified by silica gel column chromatography (n-heptane/ethyl acetate) to obtain a crude title compound (4.58 g, 14.4 mmol).

1H-NMR(400MHz,CDC13) δ

(ppm): 1.35(s, 12H),3.92,(s,3H),7.23(qd,J=1.2,8.2Hz, lH),7.40(m,2H).

[0123] Production Example 5

[0124] Synthesis of (S)- l -(2,6-dimethylpyridin-4-yl)-6-(fluoromethyl)-3-(3- methoxy-4-(trifluoromethoxy)phenyl)-5, 6,8,9 -tetrahydroimidazo Γ 1 ,5- d1 l^" l ,41oxazepine

[0125] ( 1) Synthesis of (S)-methyl 6-(fluoromethyl)-3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5, 6,8, 9-tetrahydroimidazori ,5-di r 1 ,41 oxazepine- 1 - carboxylate

[0126] A mixture of the compound obtained in Production Example 3 (200 mg, 0.761 mmol) and compound obtained in Production Example 4 (484 mg, 1.52 mmol), tetrakis(triphenylphosphine)palladium(0) (142 mg, 0.123 mmol), an aqueous sodium carbonate solution (1 M, 2.45 mL, 2.45 mmol) and DME (6 mL) was stirred under microwave irradiation at 130°C for 30 minutes. The reaction mixture was cooled to room temperature and ethyl acetate and a saturated aqueous ammonium chloride solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insolubles were separated through filtration and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (n-heptane/ethyl acetate) to obtain a title compound (319 mg). ESI-MS m/z 419 [M+H]+.

[0127] (2) Synthesis of (S)- l-bromo-6-(fluoromethyl)-3-(3-methoxy-4- (trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazorL5-di r L41oxazepine

[0128] A solution of the compound obtained in Production Example 5-( l) (319 mg) and a 5 N aqueous sodium hydroxide solution (9.9 mL, 49.5 mmol) in methanol (20 mL) was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature and acidified with a 5 N hydrochloric acid. The mixture was concentrated under reduced pressure. DMF (20 mL), potassium carbonate (2.32 g, 16.8 mmol), and NBS ( 1.99 g, 1 1.2 mmol) were added to the residue, and the mixture was stirred at room temperature for 8 hours. An aqueous sodium thiosulfate solution and ethyl acetate were added to the reaction mixture. The organic layer was separated and washed serially with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (n-heptane/ethyl acetate) to obtain a title compound ( 138 mg, 0.314 mmol).

¹H-NMR(400MHz,CDC13) δ (ppm):2.98-3.17(m,2H), 3.62-3.70(m, lH), 3.78- 3.88(m, lH),3.92(s,3H),3.98-4.06(m, lH),4.24-

4.63(m,4H),6.96(dd,J=2.0,8.2Hz, lH),7.20(d,J=2.0Hz, lH),7.28-7.33(m, lH).

[0129] (3) Synthesis of (S)- l-(2,6-dimethylpyridin-4-yl)-6-(fluoromethyl)-3- (3-methoxy-4-(trifluoromethoxy)phenyl)-5,6,8,9-tetrahydroimidazor L5- di r i ,41oxazepine

[0130] A mixture of the compound obtained in Production Example 5(2) (69.0 mg, 0.157 mmol), 2,6-dimethyl-pyridine-4-boronic acid (CAS No. 846548-44- 5; 35.6 mg, 0.236 mmol), tetrakis(triphenylphosphine)palladium(0) (89 mg,

0.077 mg), an aqueous sodium carbonate solution (2 M, 2.3 mL) and DME (8 mL) was stirred under microwave irradiation at 150°C for 1 hour. Water and ethyl acetate were added to the mixture. The organic layer was separated, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (n-heptane/ethyl acetate— > ethyl acetate/methanol) to obtain a title compound (42 mg, 0.09 mmol).

1H-NMR(400MHz,CDC13) δ

(ppm):2.56(s,6H),3.24(dd,J=2.3, 10.9Hz, lH),3.42(dd,J=3.9, 16.4Hz, lH),3.71 (t, J=1 1.5Hz, lH),3.84-3.97(m, lH),3.93(s,3H),4.06(dd,J=8.6, 14.8Hz, lH),4.28-

4.66(m,4H),7.04(dd,J=2.0,8.2Hz, lH),7.22(s,2H),7.24(d,J=2.0Hz, lH),7.34(m, l H).

ESI-MS m/z 466 [M+H] +

[0131] Example 5

[0132] Synthesis of (R)- l-(2,6-dimethylpyridin-4-yl)-3-(3-methoxy-4- (trifluoromethyl)phenyl)-6-methyl-5,6,8,9-tetrahydroimidazor L5- " L41oxazepine

[0133] ( 1) Synthesis of 2-(3-methoxy-4-(trifluoromethyl)benzamido)acetic acid

[0134] Oxalyl chloride (9.59 mL, 1 12 mmol) was added dropwise into a suspension of 3-methoxy-4-(trifluoromethyl)benzoic acid (CAS No. 276861- 63-3; 20.5 g, 93.1 mmol) and DMF (0.205 mL, 2.65 mmol) in THF (41 mL)/DCM ( 164 mL) under ice-cooling. The reaction mixture was warmed to room temperature and further stirred for 2 hours. The solvent was evaporated under reduced pressure to obtain corresponding crude acid chloride. A solution of crude acid chloride in THF (40 mL) was added dropwise into a mixture of glycine (8.39 g, 1 12 mmol), a 2 N aqueous sodium hydroxide solution (93 mL) and THF (200 mL) over a period of 15 minutes under ice-cooling. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was acidified with a 5 N hydrochloric acid under ice-cooling. Ethyl acetate was added to the mixture to separate the organic layer. The resultant organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain a title compound (25.6 g, 92.0 mmol).

¹H-NMR(400MHz,DMSO-d6) δ (ppm):3.94(s,2H),3.96(s,3H),7.57(d,J=8.2Hz, lH),7.67(s, lH),7.75(d,J=8.2Hz, l H),9.05(brs, lH).

[0135] (2) Synthesis of 2-(3-methoxy-4-(trifluoromethyl)phenyl)oxazol- 5(4H)-one

[0136] Methyl chloroformate (2.34 mL, 30.3 mmol) was added into a solution of the compound obtained in Example 5-( l) (8.00 g, 28.9 mmol) and NMM (3.33 mL, 30.3 mmol) in THF (150 mL) at - 10°C. The reaction mixture was stirred at - 10°C for 1 hour and then stirred for 2 hours while slowly warming it to room temperature. The resultant solid was separated by filtration through Celite (trademark). The filtrate was concentrated under reduced pressure to obtain a title compound (7.48 g, 28.9 mmol).

1H-NMR(400MHz,CDC13) δ (ppm): 3.95(s,3H),4.44(s,2H),7.32-7.39(m, lH),7.58-7.63(m,3H).

[0137] (3) Synthesis of (R)-methyl 3-(3-methoxy-4-(trifluoromethyl)phenyl)- 6-methyl-5,6,8,9-tetrahydroimidazor L5-di r L41oxazepine- l-carboxylate

[0138] A solution of the compound obtained in Example 5-(2) (4.16 g, 16.1 mmol) and (R)-5-methoxy-2-methyl-2,3,6,7-tetrahydro- l ,4-oxazepine (2.00 g, 14.0 mmol) in toluene (25 mL) was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The resultant residue was dissolved in methanol (30 mL). Sodium methoxide (755 mg, 14.0 mmol) was added to the mixture, then the resultant was heated under reflux. After 3 hours, the reaction mixture was cooled to room temperature and ethyl acetate and a saturated aqueous ammonium chloride solution were added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The insolubles were separated through filtration, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (n-heptane/ethyl acetate) to obtain a title compound (3.18 g, 8.27 mmol). A method for production of and (R)-5-methoxy-2-methyl- 2,3,6,7-tetrahydro- l ,4-oxazepine is described below in Example 6.

1H-NMR(400MHz,CDC13) δ (ppm):

1.24(d,J=6.6Hz,3H),3.1 1 (ddd,J=2.4, 10.9, 16.4Hz, lH),3.61 - 3.74(m,2H),3.91 (s,3H),3.96(s,3H),3.96- 4.03(m, lH),4.07(dd,J=4.7, 16.4Hz, lH),4.17- 4.25(m,2H),6.97(d,J=8.2Hz, lH),7.25(s, lH),7.64(d,J=8.2Hz, lH).

ESI-MS m/z 385 [M+H] +

[0139] (4) Synthesis of (R)- l-bromo-3-(3-methoxy-4-

(trifluoromethyl)phenyl)-6-methyl-5,6,8,9-tetrahydroimidazor L5- di ri,41oxazepine

[0140] A 2 N aqueous sodium hydroxide solution (3.31 mL) was added to a solution of the compound obtained in Example 5-(3) (3.18 g, 8.23 mmol) in ethanol (40 mL). The reaction mixture was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and acidified with a 5 N hydrochloric acid. The mixture was concentrated under reduced pressure. Ethanol (50 mL) was added to the resultant residue and the insolubles were separated through filtration. The resultant filtrate was concentrated under reduced pressure and dissolved in ethanol (5 mL) and DMF (50 mL). Potassium carbonate (2.86 g, 20.7 mmol) and NBS (2.21 g, 12.4 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 14 hours. Water and ethyl acetate were added to the mixture to separate the organic layer. The resultant organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The insolubles were separated through filtration and the filtrate was concentrated. The residue was purified by NH silica gel column chromatography (n-heptane/ethyl acetate) to obtain a title compound (2.73 g, 6.74 mmol).

¹H-NMR(400MHz,CDC13) δ (ppm): 1.24(d,J=6.3Hz,3H),2.95-

3.12(m,2H),3.57-3.65(m, lH),3.67-3.75(m, lH),3.92-

4.00(m, lH),3.95(s,3H),4.16-

4.28(m,2H),6.95(d,J=8.2Hz, lH),7.24(s, lH),7.63(d,J=8.2Hz, lH).

ESI-MS m/z 405, 407 [M+H] +

[0141] (5) Synthesis of (R)- l-(2,6-dimethylpyridin-4-yl)-3-(3-methoxy-4- (trifluoromethyl)phenyl)-6-methyl-5,6,8,9-tetrahydroimidazor L5- d1 l^" L41oxazepine

[0142] A mixture of the compound obtained in Example 5-(4) (900 mg, 2.22 mmol), 2,6-dimethyl-pyridine-4-boronic acid (402 mg, 2.67 mmol), (A- taPhos)₂PdCl₂ (79 mg, 0.1 1 1 mmol), an aqueous sodium carbonate solution (1 M, 5.55 mL) and DMF (20 mL) was stirred at 130°C for 2.5 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added to the mixture to separate the organic layer. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The resultant residue was purified serially by silica gel column chromatography (n-heptane/ethyl acetate — > ethyl acetate/methanol) and NH silica gel column chromatography (n-heptane/ethyl acetate) to obtain a title compound (750 mg, 1.74 mmol).

¹H-NMR(400MHz,CDC13) δ (ppm):1.28(d,J=6.6Hz,3H),2.56(s,6H),3.20(ddd,J=2.4,10.5,16.0Hz,lH),3.38(d d,J=4.3,16.0Hz,lH),3.64-3.71(m,lH),3.76-3.84(m,lH),3.96- 4.05(m,lH),3.97(s,3H),4.20- 4.31(m,2H),7.03(d,J=8.2Hz,lH),7.21(s,2H),7.28(s,lH),7.67(d,J=8.2Hz,lH). ESI-MS m/z 432 [M+H] +

[0143] Example 6

[0144] Synthesis of (R)-5-methoxy-2-methyl-2,3,6,7-tetrahydro-l,4- oxazepine

[0145] (1) Synthesis of (R)-l-((2,4-dimethoxybenzyl)amino)propan-2-ol

2,4-Dimethoxybenzaldehyde (CAS No. 613-45-65; 55.8 g, 336 mmol) was added to a solution of (R)-(-)-l-amino-2-propanol (CAS No.2799-16-8; 24.0 g, 320 mmol) and acetic acid (40.2 mL, 703 mmol) in THF (440 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride ( 102 g, 479 mmol) was added to the reaction liquid at room temperature, and the mixture was stirred for 18 hours. The solvent was concentrated under reduced pressure after the reaction. A 5 N aqueous sodium hydroxide solution ( 100 mL) and ethyl acetate (500 mL) were added to the resultant residue to separate the organic layer. Chloroform (300 mL) was added to the resultant water layer to separate the organic layer. The resultant organic layers were combined, and the resultant was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then the solvent was evaporated under reduced pressure. The resultant residue was filtered through NH silica gel (ethyl acetate) for purification to obtain a crude title compound (72 g).

¹H-NMR(400MHz,CDCl₃) δ (ppm): 1.13(d,J=6.3Hz,3H),2.34(dd,J=9.4, 12.1Hz, lH),2.68(dd,J=3.1 , 12.1Hz, l H),3.72(d,J=2.0Hz,2H),3.75-3.79(m, lH),3.80(s,3H),3.82(s,3H),6.39- 6.48(m,2H),7.10(d,J=8.2Hz, lH).

[0146] (2) Synthesis of (R)-N-(2,4-dimethoxybenzyl)-N-(2-hvdroxypropyl)- 3,3-dimethoxypropanamide

[0147] DIPEA ( 173 mL, 995 mmol) was added to a solution of the compound obtained in Example 6-(l) (74.7 g, 332 mmol), 3,3- dimethoxypropionic acid (CAS No. 6191-98-6; 38.5 g, 287 mmol), EDC (95 g, 497 mmol), and HOBT (67.2 g, 497 mmol) in DMF (500 mL) at room temperature, and the mixture was stirred for 14 hours. Water (1 L) and ethyl acetate (1 L) were added to the reaction mixture to separate the organic layer. The resultant organic layer was washed with water ( 1 L) and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the solvent was evaporated under reduced pressure. The resultant residue was purified by NH-silica gel column chromatography (n-heptane/ethyl acetate) to obtain a title compound (61 g, 179 mmol).

ESI-MS m/z 342 [M+H] ⁺

[0148] (3) Synthesis of (R)-4-(2,4-dimethoxybenzyl)-2-methyl-3,4-dihydro- L4-oxazepin-5(2H)-one

[0149] PPTS ( 19.7 g, 78.4 mmol) was added to a solution of the compound obtained in Example 6-(2) (53.5 g, 157 mmol) in toluene (900 mL) at room temperature, and then the mixture was heated under reflux for 7 hours. The reaction mixture was cooled to room temperature and then a saturated aqueous sodium bicarbonate solution and ethyl acetate were added to separate the organic layer. The resultant organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, the drying agent was filtered off, and then the solvent was evaporated under reduced pressure. The resultant residue was purified by silica gel column chromatography (n-heptane/ethyl acetate) to obtain a title compound (30.5 g, 1 10 mmol).

1H-NMR(400MHz,CDC13) δ (ppm):

1.19(d,J=6.6Hz,3H),3.39-3.44(m,2H),3.80(s,3H),3.82(s,3H),4.03- 4.1 1 (m, lH),4.44(d,J=14.5Hz, lH),4.73(d,J=14.5Hz, lH),5.08(d,J=8.2Hz, lH),6. 43-6.48(m,3H),7.24(d,J=9.0Hz, lH).

[0150] (4) Synthesis of (R)-4-(2,4-dimethoxybenzyl)-2-methyl- l ,4-oxazepan- 5-one

20% Palladium hydroxide/carbon (3 g, including 50% water content) was added to a solution of the compound obtained in Example 6-(3) (30.5 g, 1 10 mmol) in methanol (500 mL) at room temperature, and the mixture was stirred under hydrogen atmosphere at 40°C for 18 hours. The reaction mixture was cooled to room temperature and then was filtered through Celite®, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate) to obtain a title compound (29.1 g, 104 mmol). ¹H-NMR(400MHz,CDC13) δ (ppm): 1.05(d,J=6.6Hz,3H),2.60(dd,J=5.1 , 15.6Hz, lH),2.92(ddd,J=2.2, l 1.0, 15. 4Hz, lH), 3.20(d,J=15.2Hz, lH), 3.29-3.38(m, lH), 3.40-3.50(m, lH),3.56- 3.66(m, lH),3.81 (s,3H),3.82(s,3H),3.96(ddd,J=2.3,5.5, 12.5Hz, lH),4.37(d,J=14 .5Hz, lH),4.70(d,J=14.5Hz, lH),6.43-6.48(m,2H),7.21 (d,J=8.6Hz, lH).

[0151] (5) Synthesis of (R)-2-methyl- l ,4-oxazepan-5-one

[0152] Triethylsilane (26.2 mL, 164 mmol) was added to a solution of the compound obtained in Example 6-(4) (30.5 g, 1 10 mmol) in TFA (150 mL) at room temperature, and the mixture was stirred at 60°C for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/methanol) to obtain a title compound ( 12.3 g, 95 mmol).

¹H-NMR(400MHz,CDC13) δ (ppm):

1.19(d,J=6.3Hz,3H),2.48-

2.58(m, lH),2.89(ddd,J=2.5, 10.9, 15.4Hz, lH),3.03(ddd,J=0.9,7.6, 15.3Hz, lH),3 .35(ddd,J=3.9,8.4, 15.4Hz, lH),3.57-

3.76(m,2H),4.01 (ddd,J=2.5,5.3, 12.7Hz, lH),5.85-6.07(m, lH).

[0153] (6) Synthesis of (R)-5-methoxy-2-methyl-2,3,6,7-tetrahydro- l ,4- oxazepine

[0154] Trimethyloxonium tetrafluoroborate ( 16.8 g, 1 14 mmol) was added to a solution of the compound obtained in Example 6-(5) (13.4 g, 103 mmol) in DCM (500 mL) at room temperature, and the mixture was stirred for 18 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the organic layer was separated. DCM was added to the resultant water layer, and the organic layer was separated. The resultant organic layers were combined, the resultant was washed with a saturated aqueous sodium chloride solution, then the resultant was dried over anhydrous magnesium sulfate, and then the drying agent was filtered off and the solvent was evaporated under reduced pressure to obtain a title compound ( 13.7 g, 96 mmol).

¹H-NMR(400MHz,CDC13) δ (ppm):

1.19(d,J=6.4Hz,3H),2.42(ddd,J=1.2,4.5, 15.6Hz, lH),2.81 -2.92(m, lH),3.33- 3.42(m, lH), 3.47-3.59(m,3H),3.61 (s,3H),3.85-3.93(m, lH).

[0155] Test Example 1 :

[0156] Embodiments as reported above were characterized for specificity of binding in the brain and brain penetration using positron emission tomography (PET) in vivo in Sprague Dawley rats and common marmosets. Dynamic PET scans were conducted in isoflurane (2-3%) anesthetized Sprague Dawley rats (n=5) and propofol anesthetized (0.4 mg/kg/min) common marmosets (n=5) using a NanoPET CT camera (Mediso, Medical Imaging Systems, HU). The injected dose was 21.5 +2.9 MBq (mean + SD) for the Sprague Dawley rats and 20.2 + 3.2 MBq (mean + SD) for common marmosets. To assess maximal displacement of the tracer, a bolus + infusion paradigm was used with the compound as shown in Formula (XXXI), which is also referred to as "Compound (XXXI)", which is specific to mGluR2 and/or mGluR3 receptors, and which is shown below:

[0157] To obtain maximal occupancy of Compound (XXXI), Sprague Dawley rats were dosed with a bolus of 3.1 mg/kg + 1.8 mg/kg/hr; and common marmosets were dosed at 1.5 mg/kg bolus + 0.42 mg/kg/hr. The doses were based on the pharmacokinetics in each species. Plasma concentration of Compound (XXXI) was measured immediately prior to tracer injection. The scan was initiated at the time of tracer injection and continued for 120 minutes in each Sprague Dawley rat and 90 minutes in each common marmoset.

[0158] Summed images from 5-90 minutes of acquisition are shown for a single Sprague Dawley rat brain (in FIG. 1A, FIG. I B , FIG. 2A, and FIG. 2B), and a single common marmoset brain (in FIG. 3A, FIG. 3B, FIG. 4A, and FIG. 4B). For each species there is a transverse and sagittal image for the baseline of Compound (XXX) alone and blocked with Compound (XXXI).

[0159] The images shown in FIG. 1A through FIG. 4B were obtained at the level of the striatum. The images show uptake that is greater in the striatum and cortical regions that is reduced after the treatment with the blocking Compound (XXXI).

[0160] At the end of the dynamic scan, the data were reconstructed using the software on the NanoPET camera using OSEM algorithms. The data was binned into 23 frames with the following time points; 4 x 15 sec, 4 x 60 sec, 5 x 180 sec, 4 x 300 sec, 4 x 600 sec and 2 x 1200 sec for Sprague Dawley rats and 22 frames with the following time points 4 x 15 sec, 4 x 60 sec, 5 x 180 sec, 4 x 300 sec, and 5 x 600 sec in common marmoset. MRI generated regions of interest in the brain were placed on the CT aligned, PET reconstructed data to calculate the counts in each brain region for each frame using the VivoQuant™ program (InVicro, Boston, MA., Ver 1.2).

[0161] The count rates in MBq/mm³ were standardized to the animal weight and injected dose and reported as the standard uptake value (SUV) for each time frame. The binding potential (BP_ND) for the regions of the brain with high receptor density for mGluR2 and/or mGluR3, striatum, cortex and hippocampus in Sprague Dawley rat and putamen, cortex and hippocampus for common marmoset as well as the midbrain reference region in the Sprague Dawley rat and medulla in the common marmoset were calculated from the Logan analysis for reference region (Logan, et al., J. Cereb. Blood Flow Metab. 16:834, 1996) which calculates the distribution volume ratio (DVR), where the BP_ND = DVR- 1.

[0162] The time activity curve (TAC) for Compound (XXX) is shown in FIG.

5A for a single Sprague Dawley rat. A TAC for a single Sprague Dawley rat in the presence of a high blocking dose of Compound (XXXI) ( 1800 ng/ml measured plasma concentration) is shown in FIG. 5B. For a single common marmoset, the time activity curves under baseline conditions and in the presence of a plasma concentration of 2452 ng/ml Compound (XXXI) are shown in FIG. 6A and FIG. 6B, respectively.

[0163] In both species, the tracer Compound (XXX) in the baseline scans demonstrated the rapid uptake in all brain regions of the compounds, followed by washout in the regions which have a low receptor density (medulla, midbrain). The compounds were retained in regions of the brain that have been reported to have a high density of mGluR2 and/or mGluR3 receptors including cortex, striatum, hippocampus and cerebellum (Richards, et al., J. Comp. Neurol 487: 15, 2005). Specificity of the binding was demonstrated by blocking the binding of the PET ligands in regions of the brain displaying specific uptake with a competing non-radiolabeled compound of different structure (Compound (XXXI)).

[0164] The extrapolated BP_ND from the Logan plots are shown in Table 3 below. In marmosets 3, 4, and 5, no blocking data is shown; those animals were only used for binding level of tracer (marmosets 4 and 5) or did not receive a sufficient blocking dose for greater than 90% occupancy of the blocking compound (marmoset 3).

TABLE 3

Rat 2 0.55 0.42 0.25 0.2 0.08 0.07

Rat 3 0.57 0.38 0.30 0.13 0 0.02

Rat 4 0.79 0.58 0.33 0.14 0 0

Rat 5 0.71 0.44 0.33

Mean + 0.63 + 0.44 + 0.28 + 0.05 0.14 + 0.02 + 0.03 + 0.03 SD 0.12 0.08 0.03 0.04

Marmoset 0.65 0.60 0.48 0.1 0.04 0.19

1

Marmoset 0.47 0.28 0.41 0.10 0.04 0.1

2

Marmoset 0.54 0.54 0.3

3

Marmoset 0.77 0.75 0.52

4

Marmoset 0.67 0.58 0.34

5

Mean + 0.62 + 0.55 + 0.41 + 0.09

SD 0.12 0.17 65] The information outlined above, demonstrates the specificity of these tracers for the mGluR2 and/or mGluR3 receptors and allows the use of these PET ligands for evaluation of in vivo receptor occupancy for mGluR2 and/or mGluR3 ligand studies in mammalian species. One of skill in the art would recognize that a dose-response curve for an mGluR2 and/or mGluR3 ligand could be generated using these PET ligands.

Claims

WHAT IS CLAIMED IS :

1. A compound represented by the following Formula (XXIX) or a salt thereof:

(XXIX)

wherein at least one fluorine is fluorine- 18, at least one carbon carbon- 1 1 , at least one nitrogen is nitrogen- 13, or at least one oxygen oxygen- 15.

2. A compound represented by the following Formula (XXX) or a s thereof:

(XXX) .

3. A radioimaging composition comprising a compound of claim 1 or claim 2.

4. A method for radioimaging by positronic emission tomography, comprising:

administering to tissue in need of radioimaging an effective amount of a radioimaging composition of claim 3.

5. The method of claim 4, wherein said radioimaging includes marking tissues having at least one of an mGluR2 receptor and an mGluR3 receptor.

6. The method of claim 5, wherein said radioimaging is conducted in vivo.

7. The method of claim 5, wherein said radioimaging is conducted ex vivo.

8. Use of a compound of claim 1 or claim 2 as a marker for radioimaging.

9. A process for preparing a compound of Formula (XXX):

comprising fluorinating a compound of Formula (XXXII) with 18 F-fluoride:

5