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WO2018178923A1 - Agent d'imagerie - Google Patents

Agent d'imagerie Download PDF

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Publication number
WO2018178923A1
WO2018178923A1 PCT/IB2018/052185 IB2018052185W WO2018178923A1 WO 2018178923 A1 WO2018178923 A1 WO 2018178923A1 IB 2018052185 W IB2018052185 W IB 2018052185W WO 2018178923 A1 WO2018178923 A1 WO 2018178923A1
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WO
WIPO (PCT)
Prior art keywords
bioconjugate
pain
substance
aqueous composition
patient
Prior art date
Application number
PCT/IB2018/052185
Other languages
English (en)
Inventor
Daniel VAN DER MERWE
Helgard Pieter MEYER
Jan Rijn Zeevaart
Janine SUTHIRAM
Mike Machaba SATHEKGE
Thomas EBENHAN
Original Assignee
The South African Nuclear Energy Corporation Limited
University Of Pretoria
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The South African Nuclear Energy Corporation Limited, University Of Pretoria filed Critical The South African Nuclear Energy Corporation Limited
Publication of WO2018178923A1 publication Critical patent/WO2018178923A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins

Definitions

  • Fibromyalgia was already described as early as the nineteenth century by W.R. Gowers who used the term "fibrositis". In the 1950's, W. Graham described fibrositis as a pain syndrome in the absence of any organic disease. In 1977, Smythe and Moldofsky coined the new term "fibromyalgia" and proposed diagnostic criteria that could be used to identify patients with the fibromyalgia syndrome. In 1990 the American College of Rheumatology (ACR) published a report that aimed to redefine the diagnostic criteria for fibromyalgia by using the recognition of the diseases characteristics.
  • ACR American College of Rheumatology
  • fibromyalgia Diagnosis of fibromyalgia is still predominantly based on the ACR criteria and the amendments that were made in 2010. However there has been much criticism of these criteria over the years due to studies that have failed to show a correlation between tender point counts and clinical pain. Despite all of the information that has been gathered over the years regarding fibromyalgia, it still remains a very complex condition that is associated with persistent and debilitating pain that has a severe impact on a patient's ability to work and carry out every day activities. The awareness and understanding of this condition has improved significantly over the years, yet there are still 3 out of 4 patients that will remain undiagnosed. It is therefore evident that the development of a diagnostic technique, supporting the tender point analysis, would prove extremely beneficial to physicians faced with patients that have a myriad of symptoms.
  • Substance P belongs to a group of neuropeptides referred to as tachykinins which can be found in mammals and other animal species.
  • Substance P binds preferentially to the NK-1 receptor which is a glycoprotein with an extracellular amino-terminus and intracellular carboxyl tail. It is made up of 407 amino acid residues amounting to a relative molar mass of 46 kDa.20
  • the second and third domains of the receptor, which are membrane- spanning, are where agonist/antagonist binding takes place.
  • the Substance P/NK-1 pathway is one of the most studied neurotransmitter pathways in the central nervous system.
  • EP 1603598 describes radiolabeled conjugates based on Substance P and the uses thereof for imaging, targeting and treatment of brain tumours. It was found in EP 1603598 that the NK-1 receptor is expressed in brain tumours and can be applied for binding radiolabelled conjugates based on substance P and analogues thereof.
  • NK-1 receptor antagonists Most imaging studies involving NK-1 receptors have been focused on evaluating the effect of novel NK-1 antagonists in the human brain as part of the demand to develop antagonist-based drugs that will have therapeutic application in a range of disorders including pain and inflammation.
  • two NK-1 receptor antagonists (GR203040 and GR205171 ) were radiolabelled with 11 C and used in PET studies in rhesus monkeys. Both compounds were taken up rapidly in the brain with [ 11 C]GR205171 having almost a two-fold higher uptake than that of [ 11 C]GR203040.
  • a pre- treatment of a cold dose of GR205171 was administered in order to carry out quantitation of the receptor binding (Patlak graphical method, cerebellum was chosen as the reference region).
  • a steady time-dependent linear increase in the radioactivity was determined, suggesting a slow dissociation from the receptor which was considered useful for visualising the presence NK-1 receptor.
  • the slow dissociation and high affinity of the tracer indicates that the compound is less likely to be displaced by endogenous Substance P levels. This could make the tracer unsuitable for assessing possible changes in receptor expression that are related to Substance P release when there are physiological concerns.
  • the use of this compound was however limited since it did not reach equilibrium within the maximum scanning time that is possible for a C-1 1 radiolabelled ligand.
  • NK-1 antagonist - [ 18 F]SPA-RQ was evaluated in preclinical (guinea pig brain and rhesus monkey) and clinical studies. The compound showed an intense NK-1 receptor-specific binding signal and minimal nonspecific binding. No specific binding was observed in the cerebellum which is an area of the brain known to lack NK-1 receptors. This defined an internal reference region for determination of a background signal (i.e. non-specific accumulation of the tracer) and tracer sensitivity.
  • [ 18 F]SPA-RQ was able to penetrate the monkey brain but washed out with time from the cerebellum. Pre-treatment with cold antagonist decreased binding in the caudate and cortex and rendered no effect in the cerebellum.
  • NK-1 antagonist R1 16301 radiolabeled with C-1 1 as an in vivo tracer of NK-1 receptors in humans for the purpose of exploring the involvement of NK-1 receptors in a variety of neuropsychiatric disorders and to aid in the development of drugs that can effectively target the NK-1 receptor.
  • the biodistribution of the tracer corresponded to the known distribution of NK-1 receptors.
  • R1 16301 Following pre- administration of cold R1 16301 , a substantial reduction in the specific tracer signal to background levels was observed. This served to confirm that the tracer was selective to the NK-1 receptor.
  • An object of this invention is to provide a tool that will be useful in the diagnosis of pain, and the treatment of pain, and in particular in the diagnosis, and the treatment, of pain-related diseases such as fibromyalgia.
  • This invention relates to a bioconjugate comprising a chelating agent capable of containing a radionuclide linked to Substance P for use as an imaging agent in a method for detection of increased availability of NK-1 receptors for diagnosing pain, especially chronic pain.
  • Types of chronic pain include pain from autoimmune diseases such as spondylitis, and systemic lupus erythematosus, cancer pain, osteoarthritic pain, fibromyalgia, tendinosis, regional pain syndromes, myofascial pain syndromes, chronic pain conditions caused by central sensitization that can be seen in the dorsal horn in the spinal cord.
  • the invention has particular application in the diagnosis of fibromyalgia.
  • the chelating agent may be a bifunctional chelating agent (BFCA) which is a compound consisting of a varied number of heteroatoms, generally oxygen (O), nitrogen (N) or sulphur (S) that are able to complex a radioisotope.
  • BFCA bifunctional chelating agent
  • the BFCAs may be cyclic or acyclic. Examples of cyclic chelators are as follows:
  • Gallium-68 radiolabeled Substance P was evaluated as the imaging agent and the chelating agent is 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA).
  • DOTA 1,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid
  • the 68 Ga-DOTA-Substance P has a radiochemical purity >95.0%, preferably >98.0%.
  • the bioconjugate of the present invention is 68 Ga-DOTA-Substance P PET/CT used for detection of increased availability of NK-1 receptors in chronic pain disorders.
  • the invention also covers an aqueous composition for injection as a tracer dose in a human or animal patient may containing the bioconjugate described above in a dosage of from 1 MBq/kg to 5 MBq/kg, preferably from 2.4 MBq/kg to 4 MBq/kg.
  • the injected tracer dose in a human or animal patient may be from 2 mCi to 9.5 mCi, preferably from 4.5 mCi to 7.5 mCi.
  • the aqueous composition may be an aqueous saline solution with residual solvent content ⁇ 3% up to a total volume of 5-10 ml, for administration via an intravenous (IV) bolus injection.
  • IV intravenous
  • Fibromyalgia may be identified by identifying symmetrical pain points in one or more of the following areas of the body: the neck (back and front), the chest, the shoulders, the upper back, the lower back, the arms, the hips, the knees.
  • a second embodiment of the invention relates to the bioconjugate defined above comprising a chelating agent capable of containing a radionuclide linked to Substance P for use in a method of treating pain.
  • the radionuclide may be a therapeutic agent selected from: 188 Re, 186 Re,
  • the injected therapeutic dose in a human patient may be from 26 MBq/kg to 105 MBq/kg, preferably from 53 MBq/kg to 79 MBq/kg.
  • the injected therapeutic dose in a human patient may be from 50 mCi to 200 mCi, preferably from 100 mCi to 150 mCi.
  • the invention also covers an aqueous composition containing the bioconjugate described above for administration via an IV bolus injection.
  • the aqueous solution is saline with residual solvent content ⁇ 3% up to a total volume of 5-10 ml.
  • the invention also covers methods of diagnosis and treatment of pain using the bioconjugate defined above.
  • Figure 1 A is a radio-HPLC analysis of 68Ga-DOTA-SP
  • Figure 1 B is a maximum intensity projection image of the in vivo biodistribution in a healthy dog ;
  • Figure 1 C shows time-activity-curves yielded from blood and urine
  • Figure 2 shows a 68 Ga-DOTA-SubP-PET/CT baseline scan of a dog presenting with hip dysplasia and lameness in the leg;
  • Figure 3 shows a 68 Ga-DOTA-SubP-PET/CT re-scan of a dog presenting with hip dysplasia and lameness in the leg.
  • Figure 4 is a drawing of a human patient, with dots showing symmetrical pain points for diagnosing fibromyalgia.
  • This invention relates to the use of radionuclide labelled conjugates as imaging agents in the diagnosis of pain, and in particular in the diagnosis of pain-related diseases such as fibromyalgia.
  • An aim of the invention is to identify the pain sensation and not necessarily a disease that causes pain or the origin of the pain.
  • Radionuclide labelled conjugates of Substance P can be used as an imaging agent to detect increased Neurokinin-1 (NK-1 ) receptor availability in disorders which are characterised by chronic pain.
  • Substance P is a neuropeptide that is naturally occurring in the biological system and has long been studied for its role in nociceptive (pain) responses and neurogenic inflammation.
  • Substance P was chosen as the biomarker since it has a natural affinity for the NK-1 receptor in biological systems and has never been used to evaluate NK-1 receptor availability before.
  • a radionuclide conjugate of Substance P has already been used in oncology based applications.
  • the radionuclide labelled conjugate of Substance P comprises a chelating agent capable of containing a radionuclide bound to Substance P.
  • the chelating agent may be a bifunctional chelating agent (BFCA) which is a compound consisting of a varied number of heteroatoms, generally 0,N or S that are able to complex a radioisotope.
  • the chelating agent may be cyclic or acylic.
  • cyclic chelators are:1 ,4,7-Triazacyc!ononane (TACN);1 ,4,7- triazacyclononane-triacetic acid (NOTA);1 ,4,7-triazacyclononane-N- succinic acid-N',N"-diacetic acid(NOTASA); 1 ,4,7-triazacyclononane-N- glutamic acid-N',N"-diacetic acid(NODAGA);1 ,4,7-triazacyclononane- N,N',N"-tris (methylenephosphonic)(NOTP); 1 ,4,7,10- tetraazacyclododecane ([12]aneN4)(cyclen); 1 ,4,7,10- tetraazacyclotridecane ([13]aneN4); 1 ,4,7,1 1 -tetraazacyclotetradecane (iso- cyclam); 1 ,4,7,
  • acyclic chelators are: ethylene-diamine-tetraacetic-acid (EDTA); and diethylene-triamine-penta-acetic acid (DTPA).
  • Gallium-68 radiolabeled Substance P was evaluated as the imaging agent and the chelating agent is 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA).
  • DOTA 1,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid
  • the preferred radiolabeled product of the present invention is 68 Ga-DOTA- Substance P PET/CT used for detection of increased availability of NK-1 receptors in chronic pain disorders.
  • Ga-DOTA-Substance P was produced with a radiochemical purity >98.0%, and was assessed in healthy dogs and dogs with chronic pain (dysplasia) to determine the biodistribution of the potential imaging agent for the detection of increased presence/expression of NK-1 receptors in chronic pain disorders.
  • a diseased dog was assessed, presenting with lameness in the back legs.
  • the PET image presented unilaterally elevated uptake in the hip (associated to bone and/or soft tissue). This suggests that there was an abnormal presence of NK-1 receptors in the hip area.
  • rescanning revealed lower uptake in the respective hip area.
  • bioconjugate is administered via an IV bolus injection.
  • the compound is formulated in saline with residual solvent content ⁇ 3% up to a total volume of 5-10 ml. Any anaesthetics are administered through the arterial port.
  • Injected tracer dose varied from 2.05 MBq/kg to 9.09 MBq/kg (dogs weighed between 25 kg to 55 kg).
  • the bioconjugate is injected as an intravenous bolus. Flush the syringe with at least the same volume of saline (NaCI 0.9%). After injection in a human or animal patient, the patient is scanned in a PET scanner to obtain a PET image which is viewed to identify the bio-distribution bioconjugate, and the location of the pain.
  • fibromyalgia may be diagnosed by identifying symmetrical pain points, indicated by dots, in one or more of the following areas of the body: the neck (back and front), the chest, the shoulders, the upper back, the lower back, the arms, the hips, the knees.
  • a bioconjugate comprising a chelating agent capable of containing a radionuclide linked to Substance P for use as a therapeutic agent for treating pain, in particular the diagnosis and/or treatment of chronic pain-related diseases, such as fibromyalgia.
  • the radionuclide may be a therapeutic agent selected from:
  • the accumulation of the radiotracer in the pressure points is expected. It is known that injection of a local anesthetic/anti-inflammatory drug into the pressure points causes pain relief. It is believed that the elimination of cytokine emitting cells causing inter alia pain sensation (more radiation sensitive than normal cells or even cancer cells * ) using a therapeutic radionuclide may alleviate pain or even prove to be longer lasting therapy
  • Example 1 Determining 68 Ga-DOTA-SP biodistribution in healthy dogs
  • Methods 68 Ga was obtained by eluate fractionation from a tin-dioxide- based 68 Ga/ 68 Ge generator (0.6M HCI elute); 50 ⁇ g of sodium acetate buffered DOTA-SP (pH 3.5-4) was incubated at 95 °C for 15 min followed by purification. The radiochemical purity was determined by HPLC using an Agilent 25 cm SB column with isocratic 75% of 0.1 % TFA/H20 and 25% of 0.1 % TFNacetonitrile. Following sterile filtration, 68 Ga-DOTA-SP was injected and tracer biodistribution was demonstrated in healthy dogs using 3 static PET/CT image acquisitions up to 150 min. The SUV quantification was achieved by 3D-VOI (volume of interest) analysis. Arterial blood and urine samples were quantified.
  • 3D-VOI volume of interest
  • Figure 1 shows (A) radio-HPLC analysis (including UV registration at 214 and 254 nm wavelength) of 68Ga-DOTA-SP (red peak Reg #2), Reg #1 refers to residual free 68Ga, (B) maximum intensity projection image of the in vivo biodistribution in a healthy dog at 60 minutes after probe injection - visible uptake in urinary bladder
  • Example 2 Determining 68 Ga-DOTA-SP biodistribution in a dysplastic dog
  • a dog with suspected hip dysplasia underwent 68Ga-DOTA-SP-PET/CT imaging following bolus tracer injection.
  • the tracer's expected biodistribution was studied along with the determination of any unilateral uptake in the suspected hip area (3 static PET/CT image acquisitions up to 150 min were done).
  • the SUV quantification was achieved by 3D-VOI (volume of interest) analysis.
  • Figure 2 shows a baseline 68 Ga-DOTA-SubP-PET/CT scan of a dog presenting with hip dysplasia and lameness in the leg, injected dose was 4.5 mCi
  • Figure 3 shows 68 Ga-DOTA-SubP-PET/CT re-scan of a dog presenting with hip dysplasia and lameness in the leg after 14-day non-steroidal antiinflammatory therapy intervention, injected dose was 5.5 mCi.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un bioconjugué comprenant un agent chélatant capable de contenir un radionucléide lié à une substance P pour une utilisation en tant qu'agent d'imagerie dans un procédé de détection de disponibilité accrue de récepteurs NK-1 pour le diagnostic de la douleur, en particulier de la douleur chronique. L'invention concerne également le traitement de la douleur.
PCT/IB2018/052185 2017-03-31 2018-03-29 Agent d'imagerie WO2018178923A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1705258.0 2017-03-31
GBGB1705258.0A GB201705258D0 (en) 2017-03-31 2017-03-31 Imaging agent

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WO2018178923A1 true WO2018178923A1 (fr) 2018-10-04

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004082722A2 (fr) * 2003-03-19 2004-09-30 Universitätsspital Basel Produits radiopharmaceutiques pour le diagnostic et le traitement du cancer
WO2007035906A2 (fr) * 2005-09-21 2007-03-29 The Regents Of The University Of California Systemes, compositions et procedes pour representer localement et traiter la douleur

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004082722A2 (fr) * 2003-03-19 2004-09-30 Universitätsspital Basel Produits radiopharmaceutiques pour le diagnostic et le traitement du cancer
WO2007035906A2 (fr) * 2005-09-21 2007-03-29 The Regents Of The University Of California Systemes, compositions et procedes pour representer localement et traiter la douleur

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BREEMAN W A P ET AL: "IN VITRO AND IN VIVO STUDIES OF SUBSTANCE P RECEPTOR EXPRESSION IN RATS WITH THE NEW ANALOG [INDIUM-111-DTPA-ARG]SUBSTANCE P", THE JOURNAL OF NUCLEAR MEDICINE, SOCIETY OF NUCLEAR MEDICINE, US, vol. 37, no. 1, 1 January 1996 (1996-01-01), pages 108 - 117, XP008023981, ISSN: 0161-5505 *

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