PET of tumors expressing gastrin-releasing peptide receptor with an 18F-labeled bombesin analog

Abstract

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)NH 2, to label this analog with 18F using the new Al 18F method. In this study, the GRPR-targeting potential of 18F-labeled NOTA-8-Aoc-BBN(7-14)NH 2 was studied using 68Ga-NOTA-8-Aoc- BBN(7-14)NH 2 as a reference. Methods: The NOTA-conjugated bombesin analog was synthesized and radiolabeled with 68Ga or 18F. For 18F 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)NH 2. Small-animal PET/CT images were acquired. Results: NOTA-8-Aoc-BBN(7-14)NH 2could be efficiently labeled with 18F or with 68Ga. NOTA-8-Aoc-BBN(7-14)NH 2 was labeled with 18F 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/ mmol. The log P values of 18F- and 68Ga-labeled NOTA-8-Aoc-BBN(7-14) NH 2 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 18F- and 68Ga-labeled NOTA-8-Aoc-BBN(7-14)NH 2in 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)NH 2 after coinjection of a 100-fold excess of unlabeled NOTA-8-Aoc-BBN(7-14)NH 2peptide. The accumulation of 18F-NOTA-8-Aoc-BBN(7-14) NH 2 in the subcutaneous PC-3 tumors could be visualized via small-animal PET. Conclusion: NOTA-8-Aoc-BBN(7-14) NH 2 could be labeled rapidly and efficiently with 18F using a 1-pot, 1-step method. Radiolabeled NOTA-8-Aoc-BBN(7-14) NH 2 specifically accumulated in the GRPR-expressing PC-3 tumors and should be evaluated clinically. Copyright © 2012 by the Society of Nuclear Medicine, Inc.