PET Imaging of VPAC1 Expression in Experimental and Spontaneous Prostate Cancer

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 64 Cu-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 64 Cu and 99m Tc. 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 99m Tc-TP3939 and 64 CuCl 2. Blood clearance and in vivo stability were studied. After intravenous administration of either 64 Cu-TP3939 or 64 CuCl 2 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% 6 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 64 CuCl 2 to PC3 was nonspecific. Blood clearance was rapid. In vivo transchelation of 64 Cu-TP3939 to plasma proteins was less than 15%. 64 Cu-TP3939 uptake in PC was 7.48 6 3.63 %ID/g at 4 h and 5.78 6 0.66 %ID/g at 24 h after injection and was significantly (P , 0.05) greater than with 64 CuCl 2 (4.79 6 0.34 %ID/g and 4.03 6 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. 64 Cu-TP3939 distinctly imaged histologic grade IV prostate intraepithelial neoplasia in transgenic mice, but 18 F-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 18 F-FDG. 64 Cu-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.

Gene expression of vasoactive intestinal peptide receptors in human lung cancer

“…Vasoactive intestinal peptide/growth hormone-releasing hormone (VIP/ GHRH) antagonists, such as JV-1-52 and JV-1-53 constructed by our group, were also able to inhibit the growth of androgenindependent prostate cancers by abrogating the autocrine/ paracrine mitogenic stimuli of VIP (16). In prostate cancers, a probe specific for a 64 Cu-labeled receptor for PET imaging delineated xenografts and cases of occult prostate carcinoma that were not detectable with 18 F-FDG (17). It was shown that the VPAC1 receptor density in human lung cancer cell lines is unusually high being comparable to the density of tyrosine kinase receptors (6,18).…”

“…Based on the presence of high density VPAC1 receptors in various cancers including SCLC and NSCLC, radiolabeled VIP analogs were used to localize various primary tumors and their metastases (5,6,17,20). However, it remains to be determined if a radiolabeled VIP analog can be useful for the early detection of lung cancer.…”

Vasoactive Intestinal Peptide (VIP) and VIP Receptors-Elucidation of Structure and Function for Therapeutic Applications

“…Furthermore, VPAC1 antagonists inhibit the proliferation of breast cancer and lung cancer cells in vitro [40]. In the light of the VPAC1 overexpression in prostate and breast cancer, an experiment was performed using a VPAC1 agonist to visualize tumor localization [42].…”

Evaluation of a PACAP Peptide Analogue Labeled with 68Ga Using Two Different Chelating Agents

“…2,3 Small molecules such as sugars, amino acids, nucleic acids, or receptorbinding ligands are labeled with positron-emitting radionuclides for PET imaging to study in vivo visualization of physiological processes on a molecular level. [4][5][6][7] There are several positron-emitting radionuclides like fluorine- 18 Ga] generator, has drawn considerable attention for oncologic diagnostic applications. The short physical half-life of 68 Ga induces low radiation burden on patients and makes it an ideal radionuclide for diagnostic use.…”

“…15 In the past few years, this laboratory has designed, synthesized, and radiolabeled peptide conjugates that have high affinity for VPAC1 receptors, overexpressed in many malignant tumors, including those of the breast and prostate. [16][17][18][19][20] The peptides are analogues of pituitary adenylate cyclase-activating peptide (PACAP)-a 27 amino acid peptide and vasoactive intestinal peptide (VIP)-28 amino acid. Both have similar biochemical properties and bind to VPAC1 receptors expressed in high density on the surface of certain cancers such as of the breast, prostate, and urinary bladder (100%), colon (96%), pancreas (65%), lung (58%), stomach (54%), and liver (49%).…”