Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, USA; Department of Psychiatry, Columbia University Medical Center, New York, USA.
Department of Radiology, Wake Forest School of Medicine, Winston Salem, NC, USA.
Bioorg Med Chem Lett. 2019 Mar 15;29(6):778-781. doi: 10.1016/j.bmcl.2019.01.033. Epub 2019 Jan 25.
Dysfunction of GSK3 is implicated in the etiology of many brain, inflammatory, cardiac diseases, and cancer. PET imaging would enable in vivo detection and quantification of GSK3 and can impact the choice of therapy, allow non-invasive monitoring of disease progression and treatment effects. In this report, the synthesis and evaluation of a high affinity GSK3 ligand, [C]2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide, ([C]CMP, (3), (IC = 3.4 nM, LogP = 1.1) is described. [C]CMP was synthesized in 25 ± 5% yield by radiomethylating the corresponding phenolate using [C]CHI. The radioligand exhibited modest uptake in U251 human glioblastoma cell lines with ∼50% specific binding. MicroPET studies in rats indicated negligible blood-brain barrier (BBB) penetration of [C]CMP, despite its high affinity and suitable logP value for BBB penetration. However, administration of cyclosporine prior to [C]CMP injection showed significant improvement in brain radioactivity uptake and the tracer binding. This finding indicates that [C]CMP might be a P-gp efflux substrate and therefore has some limitations for routine in vivo PET evaluations in brain.
GSK3 功能障碍与许多脑部、炎症性、心脏疾病和癌症的病因有关。PET 成像能够在体内检测和定量检测 GSK3，并可能影响治疗选择，允许非侵入性地监测疾病进展和治疗效果。在本报告中，描述了一种高亲和力 GSK3 配体 [C]2-(环丙烷甲酰胺基)-N-(4-甲氧基吡啶-3-基)异烟酰胺 ([C]CMP，(3)，IC=3.4 nM，LogP=1.1)的合成和评价。[C]CMP 通过用 [C]CHI 放射性甲基化相应的酚盐以 25±5%的产率合成。该放射性配体在 U251 人胶质母细胞瘤细胞系中具有约 50%的特异性结合，表现出适度的摄取。尽管 [C]CMP 具有高亲和力和适合 BBB 穿透的 LogP 值，但在大鼠中的 microPET 研究表明其对血脑屏障 (BBB) 的穿透性可忽略不计。然而，在注射 [C]CMP 之前给予环孢素可显著提高脑放射性摄取和示踪剂结合。这一发现表明，[C]CMP 可能是 P-糖蛋白外排底物，因此在大脑的常规体内 PET 评估中存在一些限制。
