Nuclear Medicine and Biology ( IF 3.6 ) Pub Date : 2021-06-23 , DOI: 10.1016/j.nucmedbio.2021.06.005 Berend van der Wildt 1 , Zheng Miao 2 , Samantha T Reyes 2 , Jun H Park 2 , Jessica L Klockow 2 , Ning Zhao 2 , Alex Romero 2 , Scarlett G Guo 2 , Bin Shen 2 , Albert D Windhorst 3 , Frederick T Chin 2
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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 [11C]CH3I. Following administration to healthy mice, metabolic stability of [11C]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, [11C]BLZ945 binding was evaluated in vitro by autoradiography on mouse brain sections.
Results
BLZ945 was the most potent compound in our series with an IC50 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−1. 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
[11C]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.
中文翻译：
用于大脑中集落刺激因子 1 受体 PET 成像的 BLZ945 衍生物
背景
激酶集落刺激因子 1 受体 (CSF-1R) 最近被确定为在癌症治疗中减少肿瘤相关巨噬细胞和小胶质细胞负荷的新治疗靶点。多形性胶质母细胞瘤 (GBM) 是一种预后极差的高级癌症，巨噬细胞和小胶质细胞可占肿瘤总质量的 50%。目前，还没有可用于测量体内CSF-1R表达的非侵入性方法。这项工作的目的是开发一种 PET 示踪剂，用于大脑中 CSF-1R 受体表达的成像，用于未来 GBM 患者的选择和治疗监测。
方法
合成了BLZ945和一种可能允许氟 18 标记的衍生物，并在体外进行评估，以确定它们对 CSF-1R 的亲和力。使用[ 11 C]CH 3 I，通过脱甲基-BLZ945的N-甲基化，用碳-11对BLZ945进行放射性标记。对健康小鼠给药后，测定[ 11 C] BLZ945在血液和脑中的代谢稳定性以及活性分布体内。在基线、外排转运蛋白阻断和 CSF-1R 阻断条件下进行 PET 扫描。最后，[ 11 C] BLZ945结合通过小鼠脑切片放射自显影在体外进行评估。
结果
BLZ945是我们系列中最有效的化合物，IC 50值为 6.9 ± 1.4 nM。 BLZ945用碳11进行放射性标记，在60分钟的合成过程中，衰变校正的放射化学产率为20.7±1.1%，放射化学纯度为>95%，摩尔活性为153±34 GBq·μmol -1 。离体生物分布显示出中等的脑摄取和缓慢的清除，以及缓慢的血液清除。注射后 60 分钟， BLZ945在血浆和脑中的稳定性为 >99%。 PET 扫描证明BLZ945是外排转运蛋白的底物。观察到高脑摄取，这被证明大多是非特异性的。相应地，脑切片的体外放射自显影显示出高度的非特异性结合。
结论
[ 11 C] BLZ945 ，一种CSF-1R PET示踪剂，以高产率和纯度合成。该示踪剂对目标具有高效力，但是，在BLZ945或衍生物被转化为人类进行脑成像之前，未来的研究有必要解决非特异性结合和示踪剂流出问题。
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