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microPET and Autoradiographic Imaging of GRP Receptor Expression with ⁶⁴Cu-DOTA-[Lys³]Bombesin in Human Prostate Adenocarcinoma Xenografts

PET Imaging Science Center, University of Southern California Keck School of Medicine, Los Angeles, California

Overexpression of gastrin-releasing peptide (GRP) receptor (GRPR) in both androgen-dependent (AD) and androgen-independent (AI) human neoplastic prostate tissues provides an attractive target for prostate cancer imaging and therapy. The goal of this study was to develop ⁶⁴Cu-radiolabeled GRP analogs for PET imaging of GRPR expression in prostate cancer xenografted mice. Methods: [Lys³]bombesin ([Lys³]BBN) was conjugated with 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA) and labeled with the positron-emitting isotope ⁶⁴Cu (half-life = 12.8 h, 19% ß⁺). Receptor binding of DOTA-[Lys³]BBN and internalization of ⁶⁴Cu-DOTA-[Lys³]BBN by PC-3 prostate cancer cells were measured. Tissue biodistribution, microPET, and whole-body autoradiographic imaging of the radiotracer were also investigated in PC-3 (AI)/CRW22 (AD) prostate cancer tumor models. Results: A competitive receptor- binding assay using ¹²⁵I-[Tyr⁴]BBN against PC-3 cells yielded a 50% inhibitory concentration value of 2.2 ± 0.5 nmol/L for DOTA-[Lys³]BBN. Incubation of cells with the ⁶⁴Cu-labeled radiotracer showed temperature- and time-dependent internalization. At 37°C, >60% of the tracer was internalized within the first 15 min and uptake remained constant for 2 h. Radiotracer uptake was higher in AI PC-3 tumor (5.62 ± 0.08 %ID/g at 30 min after injection, where %ID/g is the percentage of injected dose per gram) than in AD CWR22 tumor (1.75 ± 0.05 %ID/g at 30 min after injection). Significant accumulation of the activity in GRPR-positive pancreas was also observed (10.4 ± 0.15 %ID/g at 30 min after injection). Coinjection of a blocking dose of [Lys³]BBN inhibited the activity accumulation in PC-3 tumor and pancreas but not in CWR22 tumor. microPET and autoradiographic imaging of ⁶⁴Cu-DOTA-[Lys³]BBN in athymic nude mice bearing subcutaneous PC-3 and CWR22 tumors showed strong tumor-to-background contrast. Conclusion: This study demonstrates that PET imaging of ⁶⁴Cu-DOTA-[Lys³]BBN is able to detect GRPR-positive prostate cancer.

Key Words: prostate cancer • microPET • gastrin-releasing peptide receptor • bombesin • ⁶⁴Cu

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