Auvity Sylvain, Attili Bala, Caillé Fabien, Goislard Maud, Cayla Jérôme, Hinnen Françoise, Demphel Stéphane, Brulon Vincent, Bottlaender Michel, Leroy Claire, Bormans Guy, Kuhnast Bertrand, Peyronneau Marie-Anne
CEA, INSERM, CNRS, BioMaps, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, 91400 Orsay, France.
Inserm UMR-S 1144, Faculté de Pharmacie de Paris, Université Paris-Cité, 75006 Paris, France.
ACS Pharmacol Transl Sci. 2024 Sep 13;7(10):3144-3154. doi: 10.1021/acsptsci.4c00348. eCollection 2024 Oct 11.
We have previously developed seven fluorinated analogues of A-836339 as new PET tracers for cannabinoid type 2 receptor (CBR) imaging, among which ()--(3-(2-(2-[F]fluoroethoxy)ethyl)-4,5-dimethylthiazol-2(3)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide ([F]FC0324) displayed high affinity and selectivity for CBR in healthy rats. In the present study, we have further evaluated the imaging and metabolic properties of [F]FC0324 in a rat model of human CBR overexpression in the brain (AAV-CB) and in non-human primates (NHPs). Autoradiography with AAV-CB rat brain sections exhibited a signal of [F]FC0324 8-fold higher in the ipsilateral region than in the contralateral region. Blocking with NE40, a CBR-specific agonist, resulted in a 91% decrease in the radioactivity. PET experiments showed a signal 7-fold higher in the ipsilateral region, and the specificity of [F]FC0324 for CBR in vivo was confirmed by the 80% decrease after blocking with NE40. In NHPs, brain time-activity curves displayed a fast and homogeneous distribution followed by a rapid washout, in accordance with the low amount of CBRs in healthy brain. Whole-body PET-CT suggested a high and specific uptake of the radiotracer in the spleen, a CBR-rich organ, and in the organs involved in metabolism and excretion, with a low bone uptake. In vitro metabolism with monkey liver microsomes (MLMs) led to the formation of six main hydroxylated metabolites of FC0324. Five of them were produced by human liver microsomes, being much less active than MLMs. In vivo, in NHPs, the main radiometabolite was likely to result from further oxidation of hydroxylated compounds, and parent [F]FC0324 accounted for 8 ± 3% of plasma radioactivity (at 120 min p.i.) with a low level of potential interfering radiometabolites. Furthermore, this metabolism should be significantly reduced in humans due to species differences. In conclusion, [F]FC0324 appears to be a promising candidate for further human studies with suitable kinetics, selectivity, and metabolic profile for CBR PET imaging.
我们之前已研发出七种A-836339的氟化类似物，作为用于大麻素2型受体（CBR）成像的新型正电子发射断层显像（PET）示踪剂，其中（）-（3-（2-（2-[F]氟乙氧基）乙基）-4,5-二甲基噻唑-2（3）-亚基）-2,2,3,3-四甲基环丙烷-1-甲酰胺（[F]FC0324）在健康大鼠体内对CBR表现出高亲和力和选择性。在本研究中，我们进一步评估了[F]FC0324在人脑CBR过表达大鼠模型（AAV-CB）和非人灵长类动物（NHP）中的成像及代谢特性。对AAV-CB大鼠脑切片进行放射自显影显示，[F]FC0324在同侧区域的信号比在对侧区域高8倍。用CBR特异性激动剂NE40阻断后，放射性降低了91%。PET实验显示同侧区域信号高7倍，用NE40阻断后降低80%证实了[F]FC0324在体内对CBR的特异性。在NHP中，脑内时间-活性曲线显示分布快速且均匀，随后迅速清除，这与健康脑中CBR含量低一致。全身PET-CT显示该放射性示踪剂在富含CBR的脾脏以及参与代谢和排泄的器官中有高特异性摄取，骨摄取较低。用猴肝微粒体（MLM）进行体外代谢导致形成FC0324的六种主要羟基化代谢物。其中五种由人肝微粒体产生，活性远低于MLM。在体内，在NHP中，主要放射性代谢物可能是羟基化化合物进一步氧化的结果，母体[F]FC0324占血浆放射性的8±3%（注射后120分钟），潜在干扰性放射性代谢物水平较低。此外，由于物种差异，这种代谢在人类中应会显著降低。总之，[F]FC0324似乎是一个有前景的候选物，可用于进一步的人体研究，其具有适合CBR PET成像的动力学、选择性和代谢特征。
Cochrane Database Syst Rev. 2021-4-19
Cochrane Database Syst Rev. 2017-12-22
Cochrane Database Syst Rev. 2020-1-9
Cochrane Database Syst Rev. 2018-2-6
Cochrane Database Syst Rev. 2005-7-20
Cochrane Database Syst Rev. 2008-7-16
Clin Orthop Relat Res. 2025-3-1
Eur J Nucl Med Mol Imaging. 2023-7
Int J Mol Sci. 2021-7-28
Cell. 2019-1-10
Zotero 插件