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, 18F-nifene. In attempts to develop potential antagonists, 18F-nifrolidine and 18F-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 3H-cytisine—exhibited a binding affinity of 0.36 nM. The fluorine-18 analog, 18F-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 18F-nifrolene with several other regions showing selective binding. In vivo rat PET studies exhibited rapid uptake of 18F-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 18F-nifrolene suggesting reversible binding to nicotinic receptors. PET imaging studies of 18F-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 18F-nifrolene are higher than measured for 18F-nifrolidine and 18F-nifzetidine. 18F-Nifrolene thus shows promise as a new PET imaging agent for α4β2 nAChR.

Nicotinic acetylcholine receptors (nAChRs) are downregulated in disease conditions such as Alzheimer’s and substance abuse. Presently, 123I-5-IA-85380 is used in human studies and requires over 6 hrs of scanning time, thus increases patient discomfort. We have designed and synthesized 3-iodo-5-[2-(S)-3-pyrrolinylmethoxy]pyridine (Niodene) with the aim to have faster binding kinetics compared to 123I-5-IA-85380, which may reduce scanning time and help in imaging studies. Binding affinity Ki of niodene for rat brain α4β2 receptors in brain homogenate assays using 3H-cytisine was 0.27 nM. Niodene, 10 nM displaced >95% of 18F-nifene bound to α4β2 receptors in rat brain slices. By using the iododestannylation method, 123I-niodene was obtained in high radiochemical purity (>95%) but with low radiochemical yield (<5%) and low specific activity (~100 Ci/mmol). Autoradiograms show 123I-niodene localized in the thalamus and cortex, which was displaced by nicotine (thalamus to cerebellum ratio = 4; cortex to cerebellum ratio = 1.6). Methods of radioiodination need to be further evaluated in order to obtain 123I-niodene in higher radiochemical yields and higher specific activity of this potentially useful new SPECT imaging agent.