title: Imaging CXCR4 expression in human cancer xenografts: evaluation of monocyclam 64Cu-AMD3465.
abstract: The chemokine receptor 4 (CXCR4) is overexpressed in several cancers and metastases and as such presents an enticing target for molecular imaging of metastases and metastatic potential of the primary tumor. CXCR4-based imaging agents could also be useful for diagnosis, staging, and therapeutic monitoring. Here we evaluated a positron-emitting monocyclam analog, (64)Cu-{N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine} ((64)Cu-AMD3465), in subcutaneous U87 brain tumors and U87 tumors stably expressing CXCR4 (U87-stb-CXCR4) and in colon tumors (HT-29) using dynamic and whole-body PET supported by ex vivo biodistribution studies. Both dynamic and whole-body PET/CT studies show specific accumulation of radioactivity in U87-stb-CXCR4 tumors, with the percentage injected dose per gram reaching a maximum of 102.70 ± 20.80 at 60 min and tumor-to-muscle ratios reaching a maximum of 362.56 ± 153.51 at 90 min after injection of the radiotracer. Similar specificity was also observed in the HT-29 colon tumor model. Treatment with AMD3465 inhibited uptake of radioactivity by the tumors in both models. Our results show that (64)Cu-AMD3465 is capable of detecting lesions in a CXCR4-dependent fashion, with high target selectivity, and may offer a scaffold for the synthesis of clinically translatable agents.
authors.affiliation: Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland 21231, USA.
authors.forename: Ravindra A
authors.initials: RA
authors.lastname: De Silva
authors.forename: Kevin
authors.initials: K
authors.lastname: Peyre
authors.forename: Mrudula
authors.initials: M
authors.lastname: Pullambhatla
authors.forename: James J
authors.initials: JJ
authors.lastname: Fox
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: Sridhar
authors.initials: S
authors.lastname: Nimmagadda
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000000981:diagnostic imaging*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging; D003301:Copper Radioisotopes; D005260:Female; D005434:Flow Cytometry; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D009368:Neoplasm Transplantation / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D012995:Solubility; D014018:Tissue Distribution; D014915:Whole-Body Counting
chemical_list: C514936:CXCR4 protein, mouse; D003301:Copper Radioisotopes; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D011725:Pyridines; D019275:Radiopharmaceuticals; D019718:Receptors, CXCR4