Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals — Radiosynthesis and ex vivo biodistribution of [¹⁸F]3-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine

Abstract

Muscarinic receptors have been implicated in neurological disorders including Alzheimer's disease, Parkinson's disease, and schizophrenia. Nineteen derivatives of thiadiazolyltetrahydropyridine (TZTP), a core that has previously shown high affinities towards muscarinic receptor subtypes, were synthesized and evaluated via in vitro binding assays. The title compound, a fluoro-polyethyleneglycol analog of TZTP (4c), was subsequently labelled with fluorine-18. Fluorine-18-labelled 4c was produced, via an automated synthesis, in an average radiochemical yield of 36% (uncorrected for decay), with high radiochemical purity (>99%) and high specific activity (326 GBq/mmol; end-of-bombardment), within 40 min (n = 3). Ex vivo biodistribution studies following tail-vein injection of [ 18 F]4c in conscious rats displayed sufficient brain uptake (0.4%-0.7% injected dose / gram of wet tissue in all brain regions at 5 min post injection); however, there were substantial polar metabolites present in the brain, thereby precluding future use of [ 18 F]4c for imaging in the central nervous system. Key words: fluorine-18, muscarinic receptor, thiadiazolyltetrahydropyridine (TZTP), positron emission tomography (PET).Résumé : Les récepteurs muscariniques ont été impliqués dans des désordres neurologiques, dont la maladie d'Alzheimer, la maladie de Parkinson et la schizophrénie. On a réalisé la synthèse de dix-neuf dérivés de la thiadiazolyltétrahydropyri-dine (TZTP), un produit fondamental pour lequel des études antérieures ont permis de montrer de grandes affinités vis-à-vis des sous-types de récepteurs muscarinique, et on a évalué leurs propriétés par des essais de fixation in vitro. On a subséquemment marqué au fluor-18 le composé mentionné dans le titre (4c), un analogue fluoropolyéthylèneglycol de la TZTP. Le composé 4c marqué au fluor-18 a été obtenu, par le biais d'une synthèse automatisée, avec un rendement radiochimique de 36 % (non corrigé pour la décroissance), avec une pureté radiochimique élevée (>99 %) et une activité spéci-fique élevée (326 GBq/mmol; fin du bombardement), en moins de 40 minutes (n = 3). Des études de biodistribution ex vivo à la suite d'injectons dans la veine de la queue du [ 18 F]4c dans des rats conscients ont démontré qu'il y se produit une absorption suffisante par le cerveau (0,4 à 0,7 % de la dose injectée / gramme de tissu mouillé dans toutes les régions du cerveau cinq minutes après l'injection) ; toutefois, plusieurs métabolites polaires sont présents dans le cerveau et cette situation élimine l'usage dans le futur du [ 18 F]4c pour faire de l'imagerie du système nerveux central. Mots-clés :fluor-18, récepteur muscarinique, thiadiazolyltétrahydropyridine (TZTP), tomographie à émission de positon (TEP).[Traduit par la Rédaction]

Controlling the crystal structure of precisely spaced polyethylene-like polyphosphoesters

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Less Exploited GPCRs in Precision Medicine: Targets for Molecular Imaging and Theranostics

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