Stanford University, School of Medicine, Department of Radiology, Molecular Imaging Program at Stanford (MIPS), 1201 Welch Road, PS049, Stanford, CA 94305-5484, USA; Amsterdam UMC, Vrije Universiteit Amsterdam, Radiology & Nuclear Medicine, de Boelelaan 1117, Amsterdam, Netherlands.
Amsterdam UMC, Vrije Universiteit Amsterdam, Radiology & Nuclear Medicine, de Boelelaan 1117, Amsterdam, Netherlands.
Bioorg Med Chem. 2021 Jul 15;42:116245. doi: 10.1016/j.bmc.2021.116245. Epub 2021 May 30.
Pharmacological targeting of tumor associated macrophages and microglia in the tumor microenvironment is a novel therapeutic strategy in the treatment of glioblastoma multiforme. As such, the colony stimulating factor-1 receptor (CSF-1R) has been identified as a druggable target. However, no validated companion diagnostic marker for these therapies exists to date. Towards development of a CSF-1R PET tracer, a set of six compounds based on recently reported CSF-1R inhibitor 5-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)nicotinamide (Compound 5) was designed, synthesized and evaluated in vitro for potency and selectivity. The highest affinity for CSF-1R was found for compound 5 (IC: 2.7 nM). Subsequent radiosynthesis of [C]5 was achieved in 2.0 ± 0.2% yield (decay corrected to start of synthesis) by carbon-11 carbon monoxide aminocarbonylation in 40 min after end of bombardment. In vitro autoradiography with [C]5 on rat brain sections demonstrated high specific binding, but also strong off-target binding. Ex vivo, only intact tracer was observed in blood plasma at 90 min post injection in healthy rats. PET scanning results demonstrated negligible brain uptake under baseline conditions and this brain uptake did not increase by blocking of efflux transporters using Tariquidar. To conclude, [C]5 was successfully synthesized and evaluated in healthy rats. However, the inability of [C]5 to cross the blood-brain-barrier excludes its use for imaging of CSF-1R expression in the brain.
在肿瘤微环境中靶向肿瘤相关巨噬细胞和小胶质细胞的药物治疗是多形性胶质母细胞瘤治疗的新策略。因此，集落刺激因子-1 受体 (CSF-1R) 已被确定为可药物治疗的靶点。然而，迄今为止，这些治疗方法还没有经过验证的伴随诊断标志物。为了开发 CSF-1R PET 示踪剂，设计、合成了一组基于最近报道的 CSF-1R 抑制剂 5-(1-甲基-1H-吡唑-4-基)-N-(2-甲基-5-(3-(三氟甲基)苯甲酰胺基)苯基)烟酰胺（化合物 5）的 6 种化合物，并对其体外效力和选择性进行了评估。对 CSF-1R 的亲和力最高的是化合物 5（IC：2.7 nM）。随后，通过 11C 一氧化碳氨甲酰化反应，在 40 分钟内（从开始合成时校正衰变）以 2.0±0.2%的产率（校正至开始合成时的衰变）实现了 [C]5 的放射性合成。用 [C]5 在大鼠脑切片上进行的体外放射自显影显示了高特异性结合，但也有很强的非靶结合。在健康大鼠中，注射后 90 分钟，仅在血血浆中观察到完整的示踪剂。PET 扫描结果表明，在基线条件下大脑摄取可忽略不计，并且使用 Tariquidar 阻断外排转运体后，大脑摄取没有增加。总之，[C]5 已成功合成并在健康大鼠中进行了评估。然而，[C]5 无法穿过血脑屏障，排除了其用于脑内 CSF-1R 表达成像的用途。
