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Synthesis and Biologic Evaluation of a Novel Serotonin 5-HT_1A Receptor Radioligand, ¹⁸F-Labeled Mefway, in Rodents and Imaging by PET in a Nonhuman Primate

¹ Brain Imaging Center, Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, California; and ² Department of Nuclear Medicine/PET, Kettering Medical Center, Dayton, Ohio

Correspondence: For correspondence or reprints contact: Jogesh Mukherjee, PhD, Department of Psychiatry and Human Behavior, Brain Imaging Center, 162 Irvine Hall, University of California, Irvine, Irvine, CA 92697-3960. E-mail: j.mukherjee{at}uci.edu

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-(2'-methoxyphenyl)-1-[2'-(N-2''-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/µmol at the end of synthesis. In vitro binding of ¹⁸F-mefway in the hippocampus (Hp), colliculus (Co), cortex (Ctx), and other brain regions—with limited binding in the cerebellum (Cer)—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.

Key Words: serotonin 5-HT_1A receptors • PET • autoradiography • ¹⁸F-mefway

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