Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine , Imperial College London , Hammersmith Hospital Campus, Du Cane Road , London W12 0NN , U.K.
Mol Pharm. 2019 May 6;16(5):2106-2117. doi: 10.1021/acs.molpharmaceut.9b00069. Epub 2019 Apr 3.
In humans, C-X-C chemokine receptor type 4 (CXCR4) is a protein that is encoded by the CXCR4 gene and binds the ligand CXCL12 (also known as SDF-1). The CXCR4-CXCL12 interaction in cancer elicits biological activities that result in tumor progression and has accordingly been the subject of significant investigation for detection and treatment of the disease. Peptidic antagonists have been labeled with a variety of radioisotopes for the detection of CXCR4, but the methodology utilizing small molecules has predominantly used radiometals. We report here the development of a F-radiolabeled cyclam-based small molecule radioprobe, [F]MCFB, for imaging CXCR4 expression. The IC value of [F]MCFB for CXCR4 was similar to that of AMD3465 (111.3 and 89.8 nM, respectively). In vitro binding assays show that the tracer depicted a differential CXCR4 expression, which was blocked in the presence of AMD3465, demonstrating the specificity of [F]MCFB. Positron emission tomography (PET) imaging studies showed a distinct uptake of the radioprobe in lymphoma and breast cancer xenografts. High liver and kidney uptakes were seen with [F]MCFB, leading us to further examine the basis of its pharmacokinetics in relation to the tracer's cationic nature and thus the role of organic cation transporters (OCTs). Substrate competition following the intravenous injection of metformin led to a marked decrease in the urinary excretion of [F]MCFB, with moderate changes observed in other organs, including the liver. Our results suggest involvement of OCTs in the renal elimination of the tracer. In conclusion, the F-radiolabeled monocyclam, [F]MCFB, has potential to detect tumor CXCR4 in nonhepatic tissues.
在人类中，C-X-C 趋化因子受体 4（CXCR4）是一种由 CXCR4 基因编码的蛋白质，可与配体 CXCL12（也称为 SDF-1）结合。CXCR4-CXCL12 相互作用在癌症中引发生物学活性，导致肿瘤进展，因此已成为检测和治疗该疾病的重要研究课题。已用各种放射性同位素对肽类拮抗剂进行了标记，以检测 CXCR4，但利用小分子的方法主要使用放射性金属。我们在此报告了一种基于 F-放射性标记的环脒小分子放射性探针[F]MCFB 的开发，用于 CXCR4 表达的成像。[F]MCFB 对 CXCR4 的 IC 值与 AMD3465 相似（分别为 111.3 和 89.8 nM）。体外结合实验表明，示踪剂显示出不同的 CXCR4 表达，在 AMD3465 存在下被阻断，证明了[F]MCFB 的特异性。正电子发射断层扫描（PET）成像研究表明，放射性探针在淋巴瘤和乳腺癌异种移植中具有明显的摄取。[F]MCFB 显示出高肝和肾摄取，这促使我们进一步研究其药代动力学的基础与其示踪剂的阳离子性质以及有机阳离子转运体（OCTs）的作用之间的关系。静脉注射二甲双胍后的底物竞争导致[F]MCFB 的尿排泄明显减少，其他器官（包括肝脏）也观察到中度变化。我们的结果表明 OCTs 参与了示踪剂的肾脏清除。总之，F-放射性标记的单环脒[F]MCFB 有可能在非肝脏组织中检测肿瘤 CXCR4。
