Development and Evaluation of an (18)F-Radiolabeled Monocyclam Derivative for Imaging CXCR4 Expression

[Image: see text] 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 (18)F-radiolabeled cyclam-based small molecule radioprobe, [(18)F]MCFB, for imaging CXCR4 expression. The IC(50) value of [(19)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 [(18)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 [(18)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 [(18)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 (18)F-radiolabeled monocyclam, [(18)F]MCFB, has potential to detect tumor CXCR4 in nonhepatic tissues.