Imaging CXCR4 Expression in Human Cancer Xenografts: Evaluation of Monocyclam Cu-64-AMD3465

Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland 21231, USA.
Journal of Nuclear Medicine (Impact Factor: 6.16). 06/2011; 52(6):986-93. DOI: 10.2967/jnumed.110.085613
Source: PubMed


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.

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    • "This phenomenon is not CXCR4-specific binding in the liver because (a) high CXCR4 expressing organs such as the spleen do not display such high uptake of the tracer; (b) only limited liver cells express CXCR4 27-29; and (c) other tracers such as labeled T140 discussed below do not show high accumulation in the liver. Another similar small molecule, AMD3465, which structure contains one cyclam that can chelate copper-64, was also evaluated as a PET tracer for imaging CXCR4 and showed very high accumulation in CXCR4 expressing tumor (~100% ID/g), and lower but significant (40% ID/g) accumulation in the liver (Figure 1D) 30. "
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    • "Additionally, the bicyclam AMD3100 has a relatively low affinity (~651 ± 37 nM) and a structurally restricted scaffold. The same group pursued their research with monocyclam analog N-[1,4,8,11-tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine (AMD3465) to image CXCR4 expression (Figure 10) [27]. Compared with AMD3100, AMD3465 has higher affinity, reduced size, and charge [213]. "
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