Synthesis and evaluation of 2-(18)F-fluoro-5-iodo-3-[2-(S)-3,4-dehydropyrrolinylmethoxy]pyridine ((18)F-Niofene) as a potential imaging agent for nicotinic α4β2 receptors.

Nicotinic α4β2 acetylcholine receptors (nAChRs) have been implicated in various pathophysiologies including neurodegenerative diseases. Currently, 2-(18)F-A85380 (2-FA) and 5-(123)I-A85380 (5-IA) are used separately in human PET and SPECT studies respectively and require >4-6 hours of scanning. We have developed 2-fluoro-5-iodo-3-[2-(S)-3-dehydropyrrolinylmethoxy]pyridine (niofene) as a potential PET/SPECT imaging agent for nAChRs with an aim to have rapid binding kinetics similar to that of (18)F-nifene used in PET studies. Niofene exhibited a 10-fold better in vitro binding affinity in rat brain than that of nicotine. The relative binding of niofene was similar to that of niodene and twice as better as that of nifene. In vitro autoradiography in rat brain slices alongside niodene indicated selective binding of niofene to regions consistent with α4β2 receptor distribution. Niofene, 10 nM, displaced >70% of (3)H-cytisine bound to α4β2 receptors in rat brain slices. Radiolabeling of (18)F-niofene was achieved in 10-15% radiochemical yield in high specific activities >2 Ci/μmol and showed rapid in vivo kinetics similar to that of (18)F-nifene and (18)F-nifrolene. In vivo PET in rats showed rapid uptake in the brain and selective localization in receptor regions such as the thalamus (TH). Pseudoequilibrium with (18)F-niofene was achieved in 30-40 minutes, which is similar to that of (18)F-nifene. Further evaluation of (18)F-niofene as a potential PET imaging agent is underway. Future studies will be conducted to radiolabel niofene with iodine-123 for use in SPECT imaging.