BLZ945 衍生物用于脑内集落刺激因子-1 受体的 PET 成像。
BLZ945 derivatives for PET imaging of colony stimulating factor-1 receptors in the brain.
机构信息
Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, School of Medicine, Stanford, CA, USA; Amsterdam UMC, Vrije Universiteit Amsterdam, Radiology & Nuclear Medicine, de Boelelaan 1117, Amsterdam, Netherlands.
Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, School of Medicine, Stanford, CA, USA.
出版信息
Nucl Med Biol. 2021 Sep-Oct;100-101:44-51. doi: 10.1016/j.nucmedbio.2021.06.005. Epub 2021 Jun 23.
BACKGROUND
The kinase colony stimulating factor-1 receptor (CSF-1R) has recently been identified as a novel therapeutic target for decreasing tumor associated macrophages and microglia load in cancer treatment. In glioblastoma multiforme (GBM), a high-grade cancer in the brain with extremely poor prognosis, macrophages and microglia can make up to 50% of the total tumor mass. Currently, no non-invasive methods are available for measuring CSF-1R expression in vivo. The aim of this work is to develop a PET tracer for imaging of CSF-1R receptor expression in the brain for future GBM patient selection and treatment monitoring.
METHODS
BLZ945 and a derivative that potentially allows for fluorine-18 labeling were synthesized and evaluated in vitro to determine their affinity towards CSF-1R. BLZ945 was radiolabeled with carbon-11 by N-methylation of des-methyl-BLZ945 using [C]CHI. Following administration to healthy mice, metabolic stability of [C]BLZ945 in blood and brain and activity distribution were determined ex vivo. PET scanning was performed at baseline, efflux transporter blocking, and CSF-1R blocking conditions. Finally, [C]BLZ945 binding was evaluated in vitro by autoradiography on mouse brain sections.
RESULTS
BLZ945 was the most potent compound in our series with an IC value of 6.9 ± 1.4 nM. BLZ945 was radiolabeled with carbon-11 in 20.7 ± 1.1% decay corrected radiochemical yield in a 60 min synthesis procedure with a radiochemical purity of >95% and a molar activity of 153 ± 34 GBq·μmol. Ex vivo biodistribution showed moderate brain uptake and slow wash-out, in addition to slow blood clearance. The stability of BLZ945 in blood plasma and brain was >99% at 60 min post injection. PET scanning demonstrated BLZ945 to be a substrate for efflux transporters. High brain uptake was observed, which was shown to be mostly non-specific. In accordance, in vitro autoradiography on brain sections revealed high non-specific binding.
CONCLUSIONS
[C]BLZ945, a CSF-1R PET tracer, was synthesized in high yield and purity. The tracer has high potency for the target, however, future studies are warranted to address non-specific binding and tracer efflux before BLZ945 or derivatives could be translated into humans for brain imaging.
背景
激酶集落刺激因子-1 受体（CSF-1R）最近被确定为一种新的治疗靶点，可用于减少癌症治疗中与肿瘤相关的巨噬细胞和小神经胶质细胞的负荷。在多形性胶质母细胞瘤（GBM）中，大脑中的一种高级别癌症，预后极差，巨噬细胞和小神经胶质细胞可占总肿瘤质量的 50%。目前，尚无非侵入性方法可用于测量体内 CSF-1R 的表达。这项工作的目的是开发一种 PET 示踪剂，用于成像脑内 CSF-1R 受体的表达，以便为未来的 GBM 患者选择和治疗监测提供依据。
方法
合成了 BLZ945 和一种可能允许氟-18 标记的衍生物，并在体外评估其对 CSF-1R 的亲和力。通过使用 [C]CHI 对去甲 BLZ945 进行 N-甲基化，BLZ945 被碳-11 放射性标记。在健康小鼠中给药后，通过离体法测定 [C]BLZ945 在血液和大脑中的代谢稳定性和活性分布。在基线、外排转运体阻断和 CSF-1R 阻断条件下进行 PET 扫描。最后，通过小鼠脑切片的放射自显影评估 [C]BLZ945 的结合情况。
结果
BLZ945 是我们系列中最有效的化合物，IC 值为 6.9±1.4 nM。BLZ945 在 60 分钟的合成过程中以 20.7±1.1%的衰变校正放射性化学产率被放射性标记为碳-11，放射性纯度>95%，摩尔活度为 153±34 GBq·μmol。离体生物分布显示，除了缓慢的血液清除外，脑组织摄取适中，洗脱缓慢。BLZ945 在血浆和大脑中的稳定性>99%，在注射后 60 分钟。PET 扫描显示 BLZ945 是外排转运体的底物。观察到脑摄取高，但主要是非特异性的。相应地，在脑切片的体外放射自显影显示出高的非特异性结合。
结论
[C]BLZ945，一种 CSF-1R PET 示踪剂，以高产率和高纯度合成。该示踪剂对靶标具有高亲和力，但在 BLZ945 或其衍生物可用于人类脑成像之前，还需要进一步的研究来解决非特异性结合和示踪剂外排的问题。
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