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Nucl Med Biol. 2011 Nov;38(8):1183-92. doi: 10.1016/j.nucmedbio.2011.05.005. Epub 2011 Aug 9.

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

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  • 1Department of Radiology, University of California-San Diego, CA, USA.


Thalamic and extrathalamic nicotinic α4β2 receptors found in the brain have been implicated in Alzheimer's disease, Parkinson's disease, substance abuse and other disorders. We report here the development of 3-(2-(S)-azetidinylmethoxy)-5-(3'-fluoropropyl)pyridine (nifzetidine) as a new putative high-affinity antagonist for nicotinic α4β2 receptors. Nifzetidine in rat brain homogenate assays containing α4β2 sites labeled with (3)H-cytisine exhibited a binding affinity: Ki=0.67 nM. The fluorine-18 analog, 3-(2-(S)-azetidinylmethoxy)-5-(3'-(18)F-fluoropropyl)pyridine ((18)F-nifzetidine), was synthesized in 20%-40% yield, and apparent specific activity was estimated to be above 2 Ci/μmol. Rat brain slices indicated selective binding of (18)F-nifzetidine to thalamus, subiculum, striata, cortex and other regions consistent with α4β2 receptor distribution. This selective binding was displaced >85% by 150 μM nicotine. Positron emission tomography (PET) imaging studies of (18)F-nifzetidine in anesthetized rhesus monkey showed slow uptake in the various brain regions. Retention of (18)F-nifzetidine was maximal in the thalamus and lateral geniculate followed by regions of the temporal and frontal cortex. Cerebellum showed the least uptake. Thalamus to cerebellum ratio was about 2.3 at 180 min postinjection and continued to rise. (18)F-Nifzetidine shows promise as a new PET imaging agent for α4β2 nAChR. However, the slow kinetics suggests a need for >3-h PET scans for quantitative studies of the α4β2 nAChRs.

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