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

Abstract

UNLABELLED:

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 (18)F using the new Al(18)F method. In this study, the GRPR-targeting potential of (18)F-labeled NOTA-8-Aoc-BBN(7-14)NH(2) was studied using (68)Ga-NOTA-8-Aoc-BBN(7-14)NH(2) as a reference.

METHODS:

The NOTA-conjugated bombesin analog was synthesized and radiolabeled with (68)Ga or (18)F. For (18)F 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(2) could be efficiently labeled with (18)F or with (68)Ga. NOTA-8-Aoc-BBN(7-14)NH(2) was labeled with (18)F 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/μmol. The log P values of (18)F- and (68)Ga-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 (18)F- and (68)Ga-labeled NOTA-8-Aoc-BBN(7-14)NH(2) 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)NH(2) after coinjection of a 100-fold excess of unlabeled NOTA-8-Aoc-BBN(7-14)NH(2) peptide. The accumulation of (18)F-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 (18)F 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.

• Authors: Ingrid Dijkgraaf, Gerben M Franssen, William J McBride, Christopher A D'Souza, Peter Laverman, Charles J Smith, David M Goldenberg, Wim J G Oyen, Otto C Boerman
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 53 Issue 6 Pg. 947-52 (Jun 2012) ISSN: 1535-5667 [Electronic] United States
• PMID: 22570329 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fluorine Radioisotopes
• Radiopharmaceuticals
• Receptors, Bombesin
• Bombesin

Topics

• Animals
• Binding, Competitive
• Bombesin (analogs & derivatives)
• Cell Line, Tumor
• Fluorine Radioisotopes
• Humans
• Isotope Labeling
• Male
• Mice
• Mice, Inbred BALB C
• Positron-Emission Tomography (methods)
• Prostatic Neoplasms (chemistry, diagnostic imaging)
• Radiopharmaceuticals
• Receptors, Bombesin (analysis)
• Tissue Distribution