@misc{oai:repo.qst.go.jp:00076734,
 author = {Ishii, Hideki and Yamasaki, Tomoteru and Zhang, Yiding and Ming-Rong, Zhang and Ishii, Hideki and Yamasaki, Tomoteru and Zhang, Yiding and Ming-Rong, Zhang},
 month = {Sep},
 note = {Abstract:
    The introduction of 11C-labelled nitrile group to the organic compounds is one of the most attractive way for the synthesis of many types of 11C-labelled compounds such as 11C-carboxylic acids, 11C-esters, 11C-amides, 11C-tetrazoles, and so on. The most traditional way for the introduction of nitrile group to organic molecule is Rosenmund-von Brown reaction using arylhalide (iodide or bromide) and CuCN. However, introduction of 11C-nitrile group with this method is little bit complicated. Generally, a preparation of Cu11CN is conducted with 11C-anmonium cianide gas and the mixture of freshly prepared solution of sodium metabisulfate and copper(II) sulfate,[1] Thus, we have explored simpler  11C-nitrile group introduction method with Rosenmund-von Brown type reaction. Here we report the CuI-mediated 11C-cyanation of (hetero)aryl bromides and its application for synthesis of [11C]perampanel. And also preliminary in vivo evaluation in mice of [11C]perampanel was performed. 

 
Introduction:
Perampanel (2-(2-oxo-1-phenyl-5-pyridin-2-yl1,2-dihydropyridin-3-yl)benzonitrile, trade name Fycompa) is a highly selective noncompetitive AMPA receptor antagonist developed by Eisai for treatment of epileptic seizures. Perampanel is currently approved in over 55 countries including the USA, Europe, Russia and Japan. Recently, the prevention of the progression of amyotrophic lateral sclerosis (ALS) by treatment of perampanel is also reported. So far, in order to elucidate the mechanism of perampanel, radiolabelled [3H]perampanel has been synthesized.[2] [11C]perampanel has also synthesized by using of Pd(0)- or Cu(II)-mediated 11C-cyanation methods, however, in vivo PET imaging of this probe has not reported, so far.[3, 4]  Thus, we report here the synthesis of [11C]perampanel by using of CuI-mediated  11C-cyanation and its preliminary in vivo evaluation in mice. 

Methods & Results:
Authentic sample and bromophenyl precursor were prepared by according to the literature method as shown in Scheme.[4] The [11C]NH4CN, which was prepared from [11C]CO2, was reacted with bromophenyl precursor in the presence of CuI in DMF at 180 °C for 5 min to give corresponding [11C]perampanel with a decay-corrected isolated radiochemical yield (RCY) of 17±5%, molar activity of 27±19 GBq/mmol and radiochemical purity ≥ 98% with a total synthesis time of 33-36 min. The preliminary bio-distribution evaluation in normal mice was performed. PET study of [11C]perampanel showed high uptake in the intestine (SUV > 2) , liver (SUV > 1.6) , galbladder (SUV > 1.6) and bladder (SUV > 1.2) and low brain uptake (SUV < 0.4) at 30 min time point. 

References:
1. N. Oi, M. Tokunaga, M. Suzuki, Y. Nagai, Y. Nakatani, N. Yamamoto, J. Maeda, T. Minamimoto, M.-R. Zhang, T. Suhara, M. Higuchi, J. Med. Chem. 2015, 58, 8444-8462.
2. T. Hanada, Y. Hashizume, N. Tokuhara, O. Takenaka, N. Kohmura, A. Ogasawara, S. Hatakeyama, M. Ohgoh, M. Ueno, Y. Nishizawa, Epilepsia 2011, 52, 1331-1340.
3. Lee, H. G.; Milner, P. J.; Placzek, M. S.; Buchwald, S. L.; Hooker, J. M. J Am Chem Soc. 2015,137, 648-651.
4. K. J. Makaravage, X. Shao, A. F. Brooks, L. Yang, M. S. Sanford, P. J. H. Scott, Org. Lett., 2018, 20, 1530., WMIC2019でのポスター発表},
 title = {Synthesis of [11C]perampanel via CuI-mediated 11C-cyanation and its preliminary in vivo evaluation in mice},
 year = {2019}
}