@misc{oai:repo.qst.go.jp:00076129,
 author = {Mori, Wakana and Kurihara, Yusuke and Hatori, Akiko and Zhang, Yiding and Fujinaga, Masayuki and Ming-Rong, Zhang and Mori, Wakana and Kurihara, Yusuke and Hatori, Akiko and Zhang, Yiding and Fujinaga, Masayuki and Ming-Rong, Zhang},
 month = {May},
 note = {Objectives: Monoacylglycerol lipase (MAGL) is a 33 kDa member of serine hydrolase enzyme which degrades 2-arachidonylglycerol (2-AG) into arachidonic acid (AA) and glycerol. It is known that blockade of MAGL reduced levels of AA and showed anti-inflammation effects. Several PET tracers, such as [11C]JJKK-048, [11C]SAR127303, [11C]MA-PB-1, targeted for MAGL have been developed [1-3]. However, no clinically-used PET ligands was reported until now. Compound 1 was reported as a selective and potent ligand for MAGL (MAGL IC50: 0.41 nM, FAAH IC50: 0.16 μM ) [4]. The promising pharmacological property of 1 motivated us to label this compound with [11C]COCl2. Herein, we synthesized [11C]1 using [11C]COCl2 and evaluated its potential for the PET imaging of MAGL in rodent brains.
Methods: Azetidine precursor 3 was synthesized in five steps from 2 (total yield 25%) and converted into hydrochloride for labelling. The synthesis of [11C]1 was performed from the production of [11C]COCl2 to HPLC separation and formulation using a totally automated synthesis system developed in house [5]. [11C]COCl2 was trapped in THF containing 1,1,1,3,3,3-hexafluoro-2-propanol (3.1 μL, 29.8 μmol) and 1,2,2,6,6-pentamethylpiperidine (PMP; 5.4 μL, 29.8 μmol ) at 0 °C. The reaction mixture was heated at 30 °C for 3 min. A solution of precursor 3 (1.0 mg, 4.7 μmol) with PMP in THF was then added into the mixture and continuously heated 30 °C for 3 min. PET scan with [11C]1 was conducted in rats at baseline and pre-treatment administered with unlabeled 1, MAGL inhibitor (JW642) and FAAH inhibitor (URB597) respectively. Additionally, biodistribution of mouse whole body was examined at 1, 5, 15, 30 and 60 min after [11C]1 injection.
Results: [11C]1 was produced in 16-24% radiochemical yields (decay-corrected, based on 22-24 GBq of [11C]CO2), 31-84 GBq/μmol molar activity and ≥98% radiochemical purity as measured by analytical HPLC (n=5). The average total synthesis time from EOB was 44 min. In PET studies, high uptake of radioactivity (SUVmax 1.6) after the injection of [11C]1 was observed in the rat brains. By pre-treatment with unlabeled 1 or MAGL selective ligand (JW642), the radioactivity in brain was significantly decreased, while treatment with FAAH inhibitor (URB597) did not reduce the brain uptake, indicating in vivo specific binding of [11C]1 to MAGL on the brain. The biodistribution of mouse showed that high uptake of [11C]1 was observed in heart, lung, adrenal glands and brown adipose. These distribution patterns of radioactive accumulation were similar to the reported biological distribution pattern of MAGL in the rodent brains and peripheral organs [2, 6].
Conclusion: We successfully synthesized [11C]1 with [11C]COCl2 as a new PET ligand in good radiochemical yield. PET with [11C]1 showed high in vivo specific binding to MAGL in the brain. [11C]1 may be a useful PET ligand for MAGL imaging in rat brain.
References:
[1] J. W. Hicks, et al, Nucl. Med. Biol. 2014, 41, 688-694. [2] L. Wang, W. Mori, et al, Theranostics. 2016, 6, 1145-1159. [3] M. Ahamed, B. Attili, et al, Eur. J. Med. Chem. 2017, 136, 104-113. [4] C. R. Butler, E. M. Beck, A. Harris, et al, J. Med. Chem. 2017, 6, 9860-9873. [5] M. Ogawa, Y. Takada, et al, Nucl. Med. Biol. 2010, 37, 73-76. [6] R. Cheng, W. Mori, et al, J. Med. Chem. 2018, 61, 1145-1159., ISRS2019},
 title = {Synthesis and evaluation of a new PET ligand for imaging of monoacylglycerol lipase in brain},
 year = {2019}
}