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 (IC₅₀: 2.7 nM). Subsequent radiosynthesis of [¹¹C]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 [¹¹C]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, [¹¹C]5 was successfully synthesized and evaluated in healthy rats. However, the inability of [¹¹C]5 to cross the blood-brain-barrier excludes its use for imaging of CSF-1R expression in the brain.

肿瘤微环境中肿瘤相关巨噬细胞和小胶质细胞的药理学靶向是治疗多形性胶质母细胞瘤的新治疗策略。因此，集落刺激因子-1 受体 (CSF-1R) 已被确定为可药物靶点。然而，迄今为止，还没有针对这些疗法的经过验证的伴随诊断标志物。开发 CSF-1R PET 示踪剂，一组六种化合物，基于最近报道的 CSF-1R 抑制剂 5-(1-methyl-1 H -pyrazol-4-yl)- N -(2-methyl-5-( 3-（三氟甲基）苯甲酰胺基）苯基）烟酰胺（化合物5）被设计、合成并在体外评估其效力和选择性。发现化合物5对 CSF-1R 的亲和力最高(IC ₅₀ : 2.7 nM)。在轰击结束后的 40 分钟内，通过一氧化碳氨基羰基化以 2.0 ± 0.2% 的产率（衰减校正到合成开始）实现了 [ ¹¹ C] 5 的后续放射合成。用[ ¹¹ C] 5在大鼠脑切片上进行的体外放射自显影显示出高特异性结合，但也表现出强脱靶结合。离体，在健康大鼠的注射后 90 分钟，在血浆中仅观察到完整的示踪剂。PET 扫描结果表明在基线条件下脑摄取可以忽略不计，并且这种脑摄取不会通过使用 Tariquidar 阻断外排转运蛋白而增加。最后，[ ¹¹ C]5在健康大鼠中成功合成和评价。然而，[ ¹¹ C] 5不能穿过血脑屏障排除了其用于脑中CSF-1R表达成像的用途。