title: Bridged cyclams as imaging agents for chemokine receptor 4 (CXCR4).
abstract: Over-expression of chemokine receptor 4 (CXCR4) is present in a majority of cancers, has been linked to an aggressive phenotype, and may indicate the metastatic potential of primary tumor. Several CXCR4 targeted therapeutics are in clinical trials and the development of the corresponding imaging agents is an area of active interest. Previously, (64)Cu-labeled imaging agents for CXCR4 have provided clear images of CXCR4-bearing tissues in relevant experimental models but demonstrated fast washout from tissues harboring receptor. Addition of stabilizing bridges is known to provide more robust chelator-Cu(II) complexes. In addition, bridged cyclam-based CXCR4 binding agents demonstrated increased receptor residence times relative to existing agents. Based on that knowledge we synthesized several bridged cyclam analogs of AMD3465, a monocyclam-based CXCR4 imaging agent, to increase the retention time of the tracer bound to the receptor to allow for protracted imaging and improved target-to-non-target ratios. Specific accumulation of two radiolabeled, cross-bridged analogs ([(64)Cu] RAD1-24 and [(64)Cu]RAD1-52) was observed in U87-stb-CXCR4 tumors in both PET/CT imaging and biodistribution studies. At 90min post-injection of radiotracer, tumor-to-muscle and tumor-to-blood ratios reached 106.05±17.19 and 28.08±4.78, respectively, for cross-bridged pyrimidine analog [(64)Cu]RAD1-52. Receptor blockade performed in vivo denoted target binding specificity. The biodistribution and PET/CT imaging studies with the radiolabeled bridged cyclams demonstrated longer tumor retention and comparable uptake to [(64)Cu]AMD3465, though [(64)Cu]AMD3465 demonstrated superior overall pharmacokinetics.
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, 21287.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Woodard
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, 21287.
authors.forename: Ravindra A
authors.initials: RA
authors.lastname: De Silva
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, 21287.
authors.forename: Babak
authors.initials: B
authors.lastname: Behnam Azad
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, 21287.
authors.forename: Ala
authors.initials: A
authors.lastname: Lisok
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, 21287.
authors.forename: Mrudula
authors.initials: M
authors.lastname: Pullambhatla
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, 21287.
authors.forename: Wojciech
authors.initials: W
authors.lastname: G Lesniak
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, 21287.
authors.forename: Ronnie C
authors.initials: RC
authors.lastname: Mease
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, 21287.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, 21287. Electronic address: snimmag1@jhmi.edu.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Nimmagadda
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001932:Brain Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed / Q000379:methods*
chemical_list: D047029:Lactams, Macrocyclic; D019718:Receptors, CXCR4