Abstract
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 18F-radiolabeled cyclam-based small molecule radioprobe, [18F]MCFB, for imaging CXCR4 expression. The IC50 value of [19F]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 [18F]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 [18F]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 [18F]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 18F-radiolabeled monocyclam, [18F]MCFB, has potential to detect tumor CXCR4 in nonhepatic tissues.
Highlights
In humans, C−X−C chemokine receptor type 4 (CXCR4) is a seven-transmembrane domain G protein-coupled receptor that is encoded by the CXCR4 gene
We report here the development of a 18F-radiolabeled cyclam-based small molecule radioprobe, [18F]MCFB, for imaging CXCR4 expression
Organ-specific metastatic spread, for instance, has been attributed in part to the CXCR4−CXCL12 interaction,[3,4] wherein CXCR4-expressing tumor cells migrate to CXCL12rich environments such as lymph nodes, lung, liver, and bone marrow
Summary
C−X−C chemokine receptor type 4 (CXCR4) is a seven-transmembrane domain G protein-coupled receptor that is encoded by the CXCR4 gene. Binding of CXCR4 to its cognate ligand, CXCL12 ( known as SDF-1), leads to the activation of several downstream signaling pathways that control cellular responses including proliferation, survival, chemotaxis, and transcription.[1,2] These CXCR4-regulated pathways exert critical functions in development and normal physiology as well as in disease processes. CXCR4 upregulation has been reported in over 20 types of malignant cancers and is correlated with poor prognosis and an aggressive phenotype. Organ-specific metastatic spread, for instance, has been attributed in part to the CXCR4−CXCL12 interaction,[3,4] wherein CXCR4-expressing tumor cells migrate to CXCL12rich environments such as lymph nodes, lung, liver, and bone marrow. Along with the metastatic spread, the CXCR4− CXCL12 axis impacts other aspects of tumor progression, including provision of a protective niche for tumor cells in the bone marrow and supporting hypoxia-driven angiogenesis through recruitment of CXCR4-positive pro-angiogenic cells.[5,6]
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