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

Abstract

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.

Evaluation of 18F-nifene binding to α4β2 nicotinic receptors in the rat brain using microPET imaging

“…Previous in vitro studies using 10 nM of nicotine displaced 60-65% in the thalamus region and 300 μM of nicotine, 95% elimination is seen in the thalamus [2]. As expected, displacement of 18 F-nifene binding was seen in the post-nicotine challenge similar to that reported for 2-[ 18 F]F-A-85380 [17].…”

“…In order to reduce the scan time, emphasis was placed on developing a tracer with faster kinetics. We have developed 18 F-nifene (2- 18 F-fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine; Figure 1), a nicotinic α4β2 receptor agonist which is suitable for positron emission tomography (PET) imaging ( K i = 0.50 nM; [2,3]). Imaging times in nonhuman primates with 18 F-nifene [2] were reduced significantly compared to 18 F-flouroA-85380 [4].…”

Nicotinic α4β2 receptor imaging agents. Part III. Synthesis and biological evaluation of 3-(2-(S)-azetidinylmethoxy)-5-(3′-18F-fluoropropyl)pyridine (18F-nifzetidine)

“…The 3-pyridyl ethers selectively bind to α4β2 receptors unlike epibatidine analogs which bind also to α3β2 and α3β4 receptors. Several agonist-based radioligands have been explored in the literature for imaging α4β2 receptors (13, 23). Here we focused our attention towards antagonist-based imaging agents with faster binding kinetics.…”

“…On the other hand 18 F-nifene showed fast in vivo kinetics, rapid uptake and cleared rapidly from various brain regions (13). 18 F-Nifene has a unique “3,4-dehydropyrrolidine” ring system which provides for its unique imaging properties.…”

“…The moderate affinity helps in accelerating the in vivo binding kinetics as was observed with the agonist 18 F-nifene, 2 (13). Replacing halogen or hydrogen at the meta-position in 3-pyridyl ethers with an alkyl group such as propyl or butyl group, reduces agonist character and increases the antagonist character (14,15).…”