Synthesis and Biologic Evaluation of a Novel Serotonin 5-HT1A Receptor Radioligand, 18F-Labeled Mefway, in Rodents and Imaging by PET in a Nonhuman Primate

摘要

id="p-1">Serotonin 5-HT_1A receptors have been implicated in disorders of the central nervous system and, therefore, are being studied by PET. Efforts are under way to improve in vivo stability of 5-HT_1A agents currently in human use (11C-labeled N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl)cyclohexanecarboxamide [11C-WAY-100635], 4-(2a€2-methoxyphenyl)-1-[2a€2-(N-2a€3-pyridinyl)-p-18F-fluorobenzamido]ethylpiperazine [18F-MPPF], and 18F-labeled trans-4-fluoro-N-(2-[4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-N-(2-pyridyl)cyclohexanecarboxamide [18F-FCWAY]). We have synthesized N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(4-18F-fluoromethylcyclohexane)carboxamide (18F-mefway), which contains a 18F on a primary carbon to make the compound more stable to defluorination. >Methods: Radiosynthesis of 18F-mefway was performed in a single tosylate for 18F-fluoride exchange. In vitro binding studies on rat brain slices using 18F-mefway were read on a phosphor imager. Monkey PET studies were performed on a whole-body PET scanner. >Results: Binding affinity (inhibitory concentration of 50% [IC₅₀]) of mefway was 26 nmol/L and was comparable to that of WAY-100635, 23 nmol/L. Yields of 18F-mefway were 20%-30% in specific activities of 74-111 GBq/??mol at the end of synthesis. In vitro binding of 18F-mefway in the hippocampus (Hp), colliculus (Co), cortex (Ctx), and other brain regionsa€”with limited binding in the cerebellum (Cer)a€”was observed, with ratios of Hp/Cer = 82.3, Co/Cer = 45.8, and Ctx/Cer = 40. Serotonin displaced 18F-mefway from various brain regions with IC₅₀ values in the range of 169-243 nmol/L. PET studies in a rhesus monkey showed 18F-mefway binding in the fontal cortex (FC), temporal cortex (TC) including hippocampus, raphe (Rp), and other brain regions, with ratios of FC/Cer = 9.0, TC/Cer = 10, and Rp/Cer = 3.3. Plasma analysis indicated the presence of approximately 30% of 18F-mefway at 150-180 min after injection. >Conclusion: The high ratios in specific brain regions such as the hippocampus suggest that 18F-mefway has potential as a PET agent for 5HT_1A receptors.