TY - JOUR
T1 - Bridged cyclams as imaging agents for chemokine receptor 4 (CXCR4)
AU - Woodard, Lauren E.
AU - De Silva, Ravindra A.
AU - Behnam Azad, Babak
AU - Lisok, Ala
AU - Pullambhatla, Mrudula
AU - Lesniak, Wojciech G.
AU - Mease, Ronnie C.
AU - Pomper, Martin G.
AU - Nimmagadda, Sridhar
N1 - Funding Information:
We would like to thank the University of Wisconsin for supplying 64 CuCl 2 and Gilbert Green for PET/CT imaging assistance and Dr. Marie-France Penet for critical reading of the manuscript. This work was supported by R01CA166131 (SN), The Alexander and Margaret Stewart Trust (SN), DOD W81XWH-12-BCRP-IDEA (SN), and resources provided through P30 CA006973 and P50 CA103175.
PY - 2014/8
Y1 - 2014/8
N2 - 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, 64Cu-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 ([64Cu] RAD1-24 and [64Cu]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 [64Cu]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 [64Cu]AMD3465, though [64Cu]AMD3465 demonstrated superior overall pharmacokinetics.
AB - 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, 64Cu-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 ([64Cu] RAD1-24 and [64Cu]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 [64Cu]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 [64Cu]AMD3465, though [64Cu]AMD3465 demonstrated superior overall pharmacokinetics.
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U2 - 10.1016/j.nucmedbio.2014.04.081
DO - 10.1016/j.nucmedbio.2014.04.081
M3 - Article
C2 - 25038987
AN - SCOPUS:84904437258
SN - 0969-8051
VL - 41
SP - 552
EP - 561
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
IS - 7
ER -