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¹⁸F-Labeled Bombesin Analogs for Targeting GRP Receptor-Expressing Prostate Cancer

¹ Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California; ² Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California; and ³ Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, California

Correspondence: For correspondence or reprints contact: Xiaoyuan Chen, PhD, Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Rd., P095, Stanford, CA 94305-5484. E-mail: shawchen{at}stanford.edu

The gastrin-releasing peptide receptor (GRPR) is found to be overexpressed in a variety of human tumors. The aim of this study was to develop ¹⁸F-labeled bombesin analogs for PET of GRPR expression in prostate cancer xenograft models. Methods: [Lys³]Bombesin ([Lys³]BBN) and aminocaproic acid-bombesin(7–14) (Aca-BBN(7–14)) were labeled with ¹⁸F by coupling the Lys³ amino group and Aca amino group, respectively, with N-succinimidyl-4-¹⁸F-fluorobenzoate (¹⁸F-SFB) under slightly basic condition (pH 8.5). Receptor-binding affinity of FB-[Lys³]BBN and FB-Aca-BBN(7–14) was tested in PC-3 human prostate carcinoma cells. Internalization and efflux of both radiotracers were also evaluated. Tumor-targeting efficacy and in vivo kinetics of both radiotracers were examined in male athymic nude mice bearing subcutaneous PC-3 tumors by means of biodistribution and dynamic microPET imaging studies. ¹⁸F-FB-[Lys³]BBN was also tested for orthotopic PC-3 tumor delineation. Metabolic stability of ¹⁸F-FB-[Lys³]BBN was determined in mouse blood, urine, liver, kidney, and tumor homogenates at 1 h after injection. Results: The typical decay-corrected radiochemical yield was about 30%–40% for both tracers, with a total reaction time of 150 ± 20 min starting from ¹⁸F^–. ¹⁸F-FB-[Lys³]BBN had moderate stability in the blood and PC-3 tumor, whereas it was degraded rapidly in the liver, kidneys, and urine. Both radiotracers exhibited rapid blood clearance. ¹⁸F-FB-[Lys³]BBN had predominant renal excretion. ¹⁸F-FB-Aca-BBN(7–14) exhibited both hepatobiliary and renal clearance. Dynamic microPET imaging studies revealed that the PC-3 tumor uptake of ¹⁸F-FB-[Lys³]BBN in PC-3 tumor was much higher than that of ¹⁸F-FB-Aca-BBN(7–14) at all time points examined (P < 0.01). The receptor specificity of ¹⁸F-FB-[Lys³]BBN in vivo was demonstrated by effective blocking of tumor uptake in the presence of [Tyr⁴]BBN. No obvious blockade was found in PC-3 tumor when ¹⁸F-FB-Aca-BBN(7–14) was used as radiotracer under the same condition. ¹⁸F-FB-[Lys³]BBN was also able to visualize orthotopic PC-3 tumor at early time points after tracer administration, at which time minimal urinary bladder activity was present to interfere with the receptor-mediated tumor uptake. Conclusion: This study demonstrates that ¹⁸F-FB-[Lys³]BBN and PET are suitable for detecting GRPR-positive prostate cancer in vivo.

Key Words: prostate cancer • GRP receptor • ¹⁸F-bombesin • microPET • microCT

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