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Synthesis and Evaluation of Nicotine ₄ß₂ Receptor Radioligand, 5-(3'-¹⁸F-Fluoropropyl)-3-(2-(S)-Pyrrolidinylmethoxy)Pyridine, in Rodents and PET in Nonhuman Primate

¹ Department of Psychiatry and Human Behavior. Brain Imaging Center, University of California, Irvine, California
² Department of Pharmacology, University of California, Irvine, California
³ Department of PET/Nuclear Medicine, Kettering Medical Center, Dayton, Ohio

Nicotine ₄ß₂ receptor subtypes are implicated in the study of Alzheimer’s disease, schizophrenia, substance abuse, lung cancer, and other disorders. We report the development and evaluation of a putative antagonist, 5-(3'-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine (nifrolidine) as a PET agent for nicotine ₄ß₂ receptors. Methods: In vitro binding affinity of nifrolidine was measured in rat brain slices labeled with ¹²⁵I-iodoepibatidine or ¹²⁵I-bungaratoxin. Selectivity of binding was measured in the presence of cytisine. ¹⁸F radiolabeling was performed by reacting the tosylate precursor with ¹⁸F-fluoride followed by deprotection. In vitro autoradiographic studies in rat brain slices with 5-(3'-¹⁸F-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine (¹⁸F-nifrolidine) were read on a phosphor imager. Rats were injected with ¹⁸F-nifrolidine (3.7 MBq each), and brain regions were counted at various times (2–120 min). Blocking studies were performed by subcutaneous injection of nicotine (10 mg/kg). A PET study of ¹⁸F-nifrolidine (approximately 148 MBq) was performed on an anesthetized rhesus monkey using a high-resolution scanner. Results: In vitro binding affinity of nifrolidine exhibited an inhibition constant of 2.89 nmol/L for the ₄ß₂ sites. Radiosynthesis and high-performance liquid chromatography purifications yielded the product in approximately 20%–40% decay-corrected radiochemical yield to provide ¹⁸F-nifrolidine specific activities of approximately 111–185 GBq/µmol. In vitro autoradiography in rat brain slices revealed selective binding of ¹⁸F-nifrolidine to the anteroventral thalamic nucleus, ventral posteriomedial thalamus, dorsolateral geniculate, and, to a lesser extent, cortex and striata, which are known to contain ₄ß₂ sites. This specific binding was completely abolished by 300 µmol/L nicotine. Ex vivo rat brain distribution studies indicated selective binding in the thalamus with a maximal thalamus-to-cerebellum ratio of approximately 3. The PET study revealed selective maximal uptake (0.01% injected dose/mL) in regions of the thalamus (anteroventral and anteromedial thalamus, ventrolateral thalamus) and extrathalamic regions such as cingulate gyrus, lateral geniculate, temporal cortex, and frontal cortex. Conclusion: Binding of ¹⁸F-nifrolidine to ₄ß₂ receptor-rich regions in rats and monkeys indicates promise as a PET agent. Additionally, the thalamus-to-cerebellum ratio approached a plateau of 1.7 in 120 min, indicating relatively faster kinetics compared with previously reported imaging agents.

Key Words: ₄ß₂ nicotine receptors • PET • ¹⁸F • nifrolidine

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