Nicotinic α4β2 receptor imaging agents. Part IV. Synthesis and Biological Evaluation of 3-(2-(S)-3,4-dehydropyrrolinylmethoxy)-5-(3’-18F-Fluoropropyl)pyridine (18F-Nifrolene) using PET

Imaging agents for nicotinic α4β2 receptors in the brain have been underway for studying various CNS disorders. Previous studies from our laboratories have reported the successful development of agonist, 18 F-nifene. In attempts to develop potential antagonists, 18 F-nifrolidine and 18 F-nifzetidine were previously reported. Further optimization of these fluoropropyl derivatives has now been carried out resulting in 3-(2-(S)-3,4-dehydropyrrolinylmethoxy)-5-(3′-Fluoropropyl)pyridine (nifrolene) as a new high affinity agent for nicotinic α4β2 receptors. Nifrolene in rat brain homogenate assays—labeled with 3 H-cytisine—exhibited a binding affinity of 0.36 nM. The fluorine-18 analog, 18 F-nifrolene, was synthesized in approximately 10–20% yield and specific activity was estimated to be >2000 Ci/mmol. Rat brain slices indicated selective binding to anterior thalamic nuclei, thalamus, subiculum, striata, cortex and other regions consistent with α4β2 receptor distribution. This selective binding was displaced >90% by 300 µM nicotine. Thalamus to cerebellum ratio (>10) was the highest for 18 F-nifrolene with several other regions showing selective binding. In vivo rat PET studies exhibited rapid uptake of 18 F-nifrolene in the brain with specific retention in the thalamus and other brain regions while clearing out from the cerebellum. Thalamus to cerebellum ratio value in the rat was >4. Administration of nicotine caused a rapid decline in the thalamic 18 F-nifrolene suggesting reversible binding to nicotinic receptors. PET imaging studies of 18 F-nifrolene in anesthetized rhesus monkey revealed highest binding in the thalamus followed by regions of the lateral cingulated and temporal cortex. Cerebellum showed the least binding. Thalamus to cerebellum ratio in the monkey brain was >3 at 120 min. These ratios of 18 F-nifrolene are higher than measured for 18 F-nifrolidine and 18 F-nifzetidine. 18 F-Nifrolene thus shows promise as a new PET imaging agent for α4β2 nAChR.