@misc{oai:repo.qst.go.jp:00076125,
 author = {Okamura, Toshimitsu and Ishii, Hideki and Kikuchi, Tatsuya and Okada, Maki and Wakizaka, Hidekatsu and Ming-Rong, Zhang and Okamura, Toshimitsu and Ishii, Hideki and Kikuchi, Tatsuya and Okada, Maki and Wakizaka, Hidekatsu and Ming-Rong, Zhang},
 month = {May},
 note = {Objectives
Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of nicotinamide and various closely related structural analogs to form positively charged pyridinium ions and contributes to the nicotinamide clearance and xenobiotic detoxification. NNMT is expressed primarily in the liver but has been found in other tissues at lower levels. Recent studies have shown relationships between changes in NNMT expression and several diseases. In the brain, Parkinson's disease patients have higher levels of NNMT protein and activity compared with normal subjects. In vivo imaging of NNMT activity would therefore be helpful for elucidation of pathological conditions. Here, we present the synthesis of [11C]nicotinamide analogs for imaging NNMT activity in the brain. To find a blood-brain barrier permeable tracer with the moderate methylation rate, which is required for NNMT imaging, five candidate tracers were designed in consideration of kinetic parameters of NNMT substrates [1].
Methods
[11C]Nicotinamide, 4-methyl[11C]nicotinamide, and 3-quinoline[11C]carboxamide were synthesized by the Pd(0)-mediated [11C]carbomethoxylation of the corresponding pinacol esters with [11C]carbon monoxide in methanol followed by hydrolysis with aqueous ammonia solution. [11C]Thionicotinamide and 4-methylpyridine-3-[11C]carbothioamide were synthesized by the thoiamidation of the corresponding [11C]cyanopyridines using sodium hydrogen sulfide in N,N-dimethylformamide (DMF) at 90°C. The [11C]cyanopyridines were prepared by the reaction of the bromo precursors with [11C]ammonium cyanide in DMF at 180°C.
Results
The radiochemical yields of the isolated [11C]nicotinamide, 4-methyl[11C]nicotinamide, 3-quinoline[11C]carboxamide, [11C]thionicotinamide, and 4-methylpyridine-3-[11C]carbothioamide from [11C]carbon dioxide were 2.7  1.1%, 4.3  3.5%, 5.4  0.1%, 7.8  6.6%, and 4.0  3.5% (decay corrected to the end of bombardment), respectively. Their radiochemical purities were >95%, and molar activity was in the range of 7.4 to 82 GBq/μmol at the end of synthesis.
Conclusions
We have achieved the synthesis of the candidate tracers, [11C]nicotinamide analogs, for imaging NNMT activity in the brain. Further in vivo studies are in progress.
References
[1] van Haren MJ et al., Biochemistry, 2016, 55, 5307−5315, ISRS2019 (the 23rd International Symposium on Radiopharmaceutical Sciences)},
 title = {Synthesis of [11C]nicotinamide analogs for imaging of nicotinamide N‑methyltransferase activity},
 year = {2019}
}