Bridged cyclams as imaging agents for chemokine receptor 4 (CXCR4)
Lauren E Woodard1, Ravindra A De Silva1, Babak Behnam Azad1
1Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, 21287.
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.
Insights
New bridged cyclam analogs show promise for improved imaging of chemokine receptor 4 (CXCR4) in cancer. These agents offer longer retention times in tumors, potentially enhancing diagnostic accuracy for aggressive cancers.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Over-expression of chemokine receptor 4 (CXCR4) is common in many cancers and linked to aggressive disease and metastasis.
- Current CXCR4-targeted imaging agents exhibit rapid washout, limiting their diagnostic utility.
- Stabilizing bridges can enhance the robustness of chelator-copper complexes and receptor residence time.
Purpose of the Study:
- To synthesize and evaluate novel bridged cyclam analogs of AMD3465 for enhanced CXCR4-targeted imaging.
- To improve tracer retention time at the receptor for protracted imaging and better target-to-non-target ratios.
Main Methods:
- Synthesis of bridged cyclam analogs of the CXCR4 imaging agent AMD3465.
- Radiolabeling of analogs with Copper-64 ([(64)Cu]).
- Evaluation using PET/CT imaging and biodistribution studies in U87-stb-CXCR4 tumor models.
- In vivo receptor blockade studies to confirm target specificity.
Main Results:
- Specific accumulation of two radiolabeled analogs, [(64)Cu] RAD1-24 and [(64)Cu] RAD1-52, was observed in U87-stb-CXCR4 tumors.
- The cross-bridged pyrimidine analog [(64)Cu]RAD1-52 achieved high tumor-to-muscle (106.05±17.19) and tumor-to-blood (28.08±4.78) ratios at 90 minutes post-injection.
- Bridged cyclams demonstrated longer tumor retention compared to [(64)Cu]AMD3465, although the latter showed superior overall pharmacokinetics.
Conclusions:
- Bridged cyclam analogs represent a promising strategy for developing improved CXCR4-targeted PET imaging agents.
- These novel agents offer enhanced tumor retention, potentially leading to improved diagnostic capabilities for CXCR4-expressing cancers.
- Further optimization is needed to balance tumor retention with overall pharmacokinetic properties for clinical translation.
