64Cu-AMD3100—A novel imaging agent for targeting chemokine receptor CXCR4

Abstract

CXCR4 is a chemokine receptor which has been shown to be exploited by various tumors for increased survival, invasion, and homing to target organs. We developed a one step radiosynthesis for labeling the CXCR4-specific antagonist AMD3100 with Cu-64 to produce 64 Cu-AMD3100 with a specific activity of 11.28 Ci/μmol (417 GBq/μmol) at the end of radiosynthesis. Incorporation of Cu(II) ion into AMD3100 did not change its ability to inhibit cellular migration in response to the (only) CXCR4 ligand, SDF-1/CXCL12. 64 Cu-AMD3100 binding affinity to CXCR4 was found to be 62.7 μM. Biodistribution of 64 Cu-AMD3100 showed accumulation in CXCR4-expressing organs and tissues, a renal clearance pathway, and an anomalous specific accumulation in the liver. We conclude that 64 Cu-AMD3100 exhibits promise as a potential PET imaging agent for visualization of CXCR4-positive tumors and metastases and might be used to guide and monitor anti-CXCR4 tumor therapy.

PET of CXCR4 Expression by a 68Ga-Labeled Highly Specific Targeted Contrast Agent

“…Other recently developed CXCR4-targeted nuclear imaging probes, including the T140 analogs 111 In-diethylenetriaminepentaacetic acid (DTPA)-Ac-TZ14011 (16) and 18 F-T140 (17), show high accumulation and retention in liver and spleen and low tumor-to-background ratios. The cyclam derivative 64 Cu-AMD3100 shows significantly higher tumor accumulation and improved tumor-to-background ratios.…”

“…The cyclam derivative 64 Cu-AMD3100 shows significantly higher tumor accumulation and improved tumor-to-background ratios. Its applicability for patient imaging, however, is challenged by high hepatic accumulation, leading to tumor-to-liver ratios less than 1 (18,19). SPECT/CT was applied for the detection of CXCR4 receptors using 125 Ilabeled antibodies (20).…”

Interrogating Tumor Metabolism and Tumor Microenvironments Using Molecular Positron Emission Tomography Imaging. Theranostic Approaches to Improve Therapeutics

“…AMD3100 is a bicyclam that can chelate a metal ion, and it was labeled with 64 Cu (Jacobson et al, 2009;Nimmagadda et al, 2010;Weiss et al, 2012). 64 Cu-AMD3100 had rapid clearance from the blood (unlike T140) and accumulation in CXCR4 expressing organs such as the bone marrow and spleen (Jacobson et al, 2009).…”

Current Molecular Imaging Positron Emitting Radiotracers in Oncology

“…Most of these are unsuitable for in vivo imaging due to the low stability and slow blood clearance of peptides and antibodies. Currently, a bicyclam CXCR4 compound, AMD3100, is the only clinical agent to target CXCR4, which can be efficiently labeled by metals, such as Cu-64, through cyclam chelation [156,157] (Fig. 6).…”