In vivo evaluation of [18F]FECUMI101 as 5-HT1AR agonist PET ligand

Objectives The 5-HT1AR plays a critical role in several major neuropsychiatric and neurodegenerative disorders. We have recently synthesized several [11C]labeled agonist ligands, of which [11C]CUMI101 has been successfully developed as a PET ligand for imaging 5-HT1AR in human brain. In our efforts to develop a F-18 ligand to facilitate clinical application, we report the radiosynthesis and in vivo evaluation of [18F]FECUMI for the quantification of 5-HT1ARs in the high affinity state.

Methods Radiolabeling of [18F]FECUMI101 was performed in 2 steps by treating purified [18F]FEOTs with 1-2 mg desmethyl-CUMI-101 in DMSO in the presence of potassium carbonate followed by RP-HPLC. PET studies using an ECAT EXACT HR+ camera in 3D mode were performed in anesthetized baboon after an i.v. bolus injection of [18F]FECUMI and dynamic imaging over 3 hrs. Metabolite analyses were performed using a RP-HPLC method.

Results FECUMI101 is a selective 5-HT1AR agonist (Ki = 0.1 nM) ligand with an Emax of 80% in GTP-gammaS binding assays in CHO cell membranes stably expressing human 5-HT1AR. Radiosynthesis of [18F]FECUMI101 was achieved in 20-30% yield (EOS, 2 steps) with a specific activity of 1-2 Ci/micromol. PET studies in isofluorine anesthetized baboon showed good uptake and that [18F]FECUMI101 was retained in 5-HT1AR rich brain areas. The free fraction of [18F]FECUMI in baboon plasma was 37 ± 4% and radioactive metabolites were found to be polar. The specificity of the ligand uptake was determined by chase studies with the specific 5-HT1A antagonist WAY100635.

Conclusions PET studies in baboon indicate that [18F]FECUMI101 selectively binds to 5-HT1AR rich brain regions. Moreover, favorable brain and plasma metabolism kinetics, measurable plasma free fraction, high selectivity and specificity suggest that [18F]FECUMI101 is a suitable candidate as an [18F]labeled agonist PET imaging agent for the in vivo quantification of high-affinity 5-HT1AR in human subjects.

Research Support R21 MH08522