PET Imaging of VPAC1 Expression in Experimental and Spontaneous Prostate Cancer

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Abstract
Among U.S. men, prostate cancer (PC) accounts for 29% of all newly diagnosed cancers. A reliable scintigraphic agent to image PC and its metastatic or recurrent lesions and to determine the effectiveness of its treatment will contribute to the management of this disease. All PC overexpresses VPAC1 receptors. This investigation evaluated a probe specific for a 64Cu-labeled receptor for PET imaging of experimental human PC in athymic nude mice and spontaneously grown PC in transgenic mice. Methods: The probe, TP3939, was synthesized, purified, and labeled with 64Cu and 99mTc. Using a muscle relaxivity assay, biologic activity was assessed and inhibitory concentrations of 50% calculated. Receptor affinity (Kd) for human PC3 cells was determined using 99mTc-TP3939 and 64CuCl2. Blood clearance and in vivo stability were studied. After intravenous administration of either 64Cu-TP3939 or 64CuCl2 in PC3 xenografts and in transgenic mice, PET/CT images were acquired. Prostate histology served as the gold standard. Organ distribution studies (percentage injected dose per gram [%ID/g]) in normal prostate were performed. The ratios of tumor to muscle, tumor to blood, normal prostate to muscle, and tumor to normal prostate were determined. Results: Chemical and radiochemical purities of TP3939 were 96.8% and 98% ± 2%, respectively. Inhibitory concentrations of 50% and affinity constants were 4.4 × 10−8 M and 0.77 × 10−9 M, respectively, for TP3939 and 9.1 × 10−8 M and 15 × 10−9 M, respectively, for vasoactive intestinal peptide 28. Binding of 64CuCl2 to PC3 was nonspecific. Blood clearance was rapid. In vivo transchelation of 64Cu-TP3939 to plasma proteins was less than 15%. 64Cu-TP3939 uptake in PC was 7.48 ± 3.63 %ID/g at 4 h and 5.78 ± 0.66 %ID/g at 24 h after injection and was significantly (P < 0.05) greater than with 64CuCl2 (4.79 ± 0.34 %ID/g and 4.03 ± 0.83 %ID/g at 4 and 24 h, respectively). The ratios of PC to normal prostate at 4 and 24 h were 4 and 2.7, respectively. 64Cu-TP3939 distinctly imaged histologic grade IV prostate intraepithelial neoplasia in transgenic mice, but 18F-FDG and CT did not. Conclusion: Data indicate that TP3939, with its uncompromised biologic activity, delineated xenografts and cases of occult PC that were not detectable with 18F-FDG. 64Cu-TP3939 is a promising probe for PET imaging of PC. It may also be useful for localizing recurrent lesions and for determining the effectiveness of its treatment.