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Evaluation of 5-¹¹C-Methyl-A-85380 as an Imaging Agent for PET Investigations of Brain Nicotinic Acetylcholine Receptors

¹ Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
² Laboratory of Genome Bio-Photonics, Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan
³ Central Research Laboratory, Hamamatsu Photonics K.K., Hamamatsu, Japan
⁴ Department of Nuclear Medicine, Graduate School of Medicine, Kyoto University, Japan

Central nicotinic acetylcholine receptors (nAChRs) represent major neurotransmitter receptors responsible for various brain functions, and changes in the density of nAChRs have recently been reported in several neurodegenerative diseases. Visualization of nAChRs in human brain has thus been of great interest, and the development of radiopharmaceuticals for the imaging and quantitative assessment of central nAChRs has been desired. In this study, we synthesized 5-¹¹C-methyl-3-(2-(S)-azetidinylmethoxy)pyridine (5MA), a derivative of 3-(2-(S)-azetidinylmethoxy)pyridine (A-85380) ¹¹C-methylated at position 5 of the pyridyl fragment, and evaluated its potential for investigating central nAChRs by PET. Methods: ¹¹C-5MA was synthesized by the incorporation of ¹¹C-methyl iodide into 5-butylstannyl A-85380, using a Pd-catalyzed coupling reaction. The affinity of 5MA for central nAChRs was measured by displacement of (–)-³H-cytisine from binding sites in rat cortical membranes. The biodistribution of ¹¹C-5MA was determined with mice. PET studies were performed on rhesus monkeys with a high-resolution PET scanner for animals. Results: The overall synthesis time was 60 min from the end of radionuclide production, and the radiochemical yield, after purification by high-performance liquid chromatography, was 30%. The radiochemical purity of the product was >99%, with a specific radioactivity of >36 GBq/µmol. In vitro receptor-binding assays demonstrated that 5MA has a high, selective binding affinity for nAChRs, being approximately 1.5-fold higher than that of A-85380, 3.5-fold higher than that of (–)-cytisine, and 10-fold higher than that of (–)-nicotine. The distribution studies in mice showed that the brain uptake of ¹¹C-5MA was profound. Regional cerebral distribution studies in mice demonstrated that the accumulation of ¹¹C-5MA was consistent with the density of nAChRs, with the highest uptake observed in the thalamus, a moderate uptake in the cortex and striatum, and the lowest uptake in the cerebellum. Furthermore, preinjection of nAChR-binding ligands, (–)-nicotine and (–)-cytisine, reduced the uptake of ¹¹C-5MA in brain regions of high uptake in the untreated experiment. PET imaging studies with ¹¹C-5MA in rhesus monkeys demonstrated clear images consistent with the distribution of nAChRs in the brain. Conclusion: These results suggest that ¹¹C-5MA is a potential PET radiopharmaceutical for nuclear medical studies of nAChRs in the brain.

Key Words: central nicotinic acetylcholine receptors • 5-¹¹C-methyl-3-(2-(S)-azetidinylmethoxy)pyridine • receptor-binding affinity • biodistribution • PET

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