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Synthesis and evaluation of nicotine alpha(4)beta(2) receptor radioligand, 5-(3 '-F-18-fluoropropyl)-3(2-(S)-pyrrolidinylmethoxy)pyridine, in rodents and PET in nonhuman primate


Nicotine alpha(4)beta(2) 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 alpha(4)beta(2) receptors. Methods: In vitro binding affinity of nifrolidine was measured in rat brain slices labeled with I-125-iodoepibatidine or I-125-bungaratoxin. Selectivity of binding was measured in the presence of cytisine. F-18 radiolabeling was performed by reacting the tosylate precursor with F-18-fluoride followed by cleprotection. In vitro autoradiographic studies in rat brain slices with 5-(3'-F-18-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine (F-18-nifrolidine) were read on a phosphor imager. Rats were injected with F-18-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 F-18-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 alpha(4)beta(2) 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/mumol. In vitro autoradiography in rat brain slices revealed selective binding of F-18-nifrolidine to the anteroventral thalamic nucleus, ventral posteriomedial thalamus, dorsolateral geniculate, and, to a lesser extent, cortex and striata, which are known to contain alpha(4)beta(2) sites. This specific binding was completely abolished by 300 mumol/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 mus, ventrolateral thalamus) and extrathalamic regions such as cingulate gyrus, lateral geniculate, temporal cortex, and frontal cortex. Conclusion: Binding of F-18-nifrolidine to alpha(4)beta(2) 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.

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