Radiosynthesis and Preclinical Evaluation of a Carbon-11 Labeled Phosphodiesterase 7 Inhibitor for PET Neuroimaging

Le résumé fourni par la source

High Resolution Image Download MS PowerPoint Slide Dysfunction of cyclic nucleotide phosphodiesterase 7 (PDE7) has been associated with excess intracellular cAMP concentrations, fueling pathogenic processes that are implicated in neurodegenerative disorders. This study aimed to develop a suitable positron emission tomography (PET) probe that allows noninvasive mapping of PDE7 in the mammalian brain. Based on a spiro cyclohexane-1,4′-quinazolinone scaffold with known inhibitory properties toward PDE7, we designed and synthesized a carbon-11 labeling tolerant methoxy analog. The resulting PET probe, code named [ 11 C]P7-2104 ( 27 ), was synthesized in high molar activities (170–220 GBq/μmol) with decay-corrected radiochemical yields of 34 ± 7%. In vitro cell uptake of [ 11 C] 27 was 6–7-fold higher in PDE7 overexpressing cells compared to the controls, whereas an in vitro specificity of up to 90% was measured. Ex vivo metabolite studies revealed a high fraction of intact parent in the rat brain (98% at 5 min and 75% at 30 min postinjection). Considerable brain penetration was further corroborated by ex vivo biodistribution and PET imaging studies, the latter showing heterogenic brain uptake. While marginal blockade was observed by PET studies in rodents, a moderate, but dose-dependent, blockade was observed in the non-human primate brain following pretreatment with nonradioactive 27 . Accordingly, [ 11 C] 27 will serve as a valuable lead compound for the development of a new arsenal of PDE7-targeted probes.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.