PET of Tumors Expressing Gastrin-Releasing Peptide Receptor with an 18F-Labeled Bombesin Analog

The gastrin-releasing peptide receptor (GRPR) is overexpressed in human prostate cancer. Bombesin (BBN) is a neurotransmitter of 14 amino acids and binds with selectivity and with high affinity to GRPRs. We have synthesized a NOTA-conjugated bombesin derivative, NOTA-8-Aoc-BBN(7-14)NH2, to label this analog with F-18 using the new (AlF)-F-18 method. In this study, the GRPR-targeting potential of F-18-labeled NOTA-8-Aoc-BBN(7-14)NH2 was studied using Ga-68-NOTA-8-Aoc-BBN(7-14)NH2 as a reference. Methods: The NOTA-conjugated bombesin analog was synthesized and radiolabeled with Ga-68 or F-18. For F-18 labeling, we used our new 1-pot, 1-step method. The labeled product was purified by reversed-phase high-performance liquid chromatography. The log P values of the radiotracers were determined. The tumor-targeting characteristics of the compounds were assessed in mice with subcutaneously growing PC-3 xenografts. GRPR-binding specificity was studied by coinjection of an excess of unlabeled NOTA-8-Aoc-BBN(7-14)NH2. Small-animal PET/CT images were acquired. Results: NOTA-8-Aoc-BBN(7-14)NH2 could be efficiently labeled with F-18 or with Ga-68. NOTA-8-Aoc-BBN(7-14)NH2 was labeled with F-18 in a single step, with 50%-90% yield. Radiolabeling, including purification, was performed in 45 min and resulted in a specific activity of greater than 10 GBq/mu mol. The log P values of F-18- and Ga-68-labeled NOTA-8-Aoc-BBN(7-14)NH2 were -1.47 +/- 0.05 and -1.98 +/- 0.03, respectively. In mice, both radiolabeled compounds cleared rapidly from the blood (<0.07 percentage injected dose per gram at 1 h after injection), mainly via the kidneys. At 1 h after injection, the uptake of F-18- and Ga-68-labeled NOTA-8-Aoc-BBN(7-14)NH2 in the PC-3 tumors was 2.15 +/- 0.55 and 1.24 +/- 0.26 percentage injected dose per gram, respectively. GRPR-binding specificity was demonstrated by reduced tumor uptake of radiolabeled NOTA-8-Aoc-BBN(7-14)NH2 after coinjection of a 100-fold excess of unlabeled NOTA-8-Aoc-BBN(7-14)NH2 peptide. The accumulation of F-18-NOTA-8-Aoc-BBN(7-14) NH2 in the subcutaneous PC-3 tumors could be visualized via small-animal PET. Conclusion: NOTA-8-Aoc-BBN(7-14) NH2 could be labeled rapidly and efficiently with F-18 using a 1-pot, 1-step method. Radiolabeled NOTA-8-Aoc-BBN(7-14) NH2 specifically accumulated in the GRPR-expressing PC-3 tumors and should be evaluated clinically.