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Abstract：
The synthesis, biochemical evaluation and radiosynthesis of a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor and radioligand was performed. NT431, a newly synthesized 4-fluorobenzyl-abemaciclib, exhibited high potency to CDK4/6 and against four cancer cell lines with IC50 similar to that of the parent abemaciclib. We performed a two-step one-pot radiosynthesis to produce [18F]NT431 with good radiochemical yield (9.6 ± 3%, n = 3, decay uncorrected), high radiochemical purity (>95%), and high molar activity (>370 GBq/µmol (>10.0 Ci/µmol). In vitro autoradiography confirmed the specific binding of [18F]NT431 to CDK4/6 in brain tissues. Dynamic PET imaging supports that both [18F]NT431 and the parent abemaciclib crossed the BBB albeit with modest brain uptake. Therefore, we conclude that it is unlikely that NT431 or abemaciclib (FDA approved drug) can accumulate in the brain in sufficient concentrations to be potentially effective against breast cancer brain metastases or brain cancers. However, despite the modest BBB penetration, [18F]NT431 represents an important step towards the development and evaluation of a new generation of CDK4/6 inhibitors with superior BBB penetration for the treatment and visualization of CDK4/6 positive tumors in the CNS. Also, [18F]NT431 may have potential application in peripheral tumors such as breast cancer and other CDK4/6 positive tumors.
摘要：
合成,进行了细胞周期蛋白依赖性激酶4和6（CDK4/6）抑制剂和放射性配体的生化评估和放射合成。NT431，一种新合成的4-氟苄基-abemaciclib，对CDK4/6和对四种癌细胞系表现出很高的效力，其IC50与亲本abemaciclib相似。我们进行了两步一锅放射合成，以产生具有良好放射化学产率（9.6±3％，n=3，衰减未校正)，高放射化学纯度（>95％），和高摩尔活性（>370GBq/µmol（>10.0Ci/µmol）。体外放射自显影证实[18F]NT431与脑组织中CDK4/6的特异性结合。动态PET成像支持[18F]NT431和亲本abemaciclib穿过BBB，尽管大脑摄取适度。因此,我们得出的结论是,NT431或abemaciclib(FDA批准的药物)不太可能以足够的浓度在脑中积累,从而可能有效对抗乳腺癌脑转移或脑癌.然而,尽管BBB渗透率不高，[18F]NT431代表了开发和评估新一代CDK4/6抑制剂的重要一步，该抑制剂具有优异的BBB渗透性，用于治疗和可视化CNS中的CDK4/6阳性肿瘤。此外，[18F]NT431可能在周围肿瘤如乳腺癌和其他CDK4/6阳性肿瘤中具有潜在的应用。
