¹⁸F-Labeled Bombesin Analog for Specific and Effective Targeting of Prostate Tumors Expressing Gastrin-Releasing Peptide Receptors

Abstract

Bombesin is a peptide exhibiting high affinity for the gastrinreleasing peptide receptor (GRPr), which is highly overexpressed on prostate cancer cells. In the present study, we developed an 18 F-labeled bombesin analog, 18 F-BAY 86-4367, which is currently being clinically tested for use in PET of prostate cancer. Methods: In vitro pharmacologic studies were performed to characterize the nonradioactive ( 19 F) standard of the bombesin analog for binding affinity and selectivity for GRPr. The stability of 18 F-BAY 86-4367 was determined in murine and human plasma. In vivo, the tumor-targeting potential and pharmacokinetic profile of the 18 F tracer were analyzed with biodistribution experiments and PET studies of prostate tumor-bearing mice. Results: The nonradioactive ( 19 F) standard of the bombesin analog showed subnanomolar and GRPr-selective binding affinity. The stability of the tracer in murine and human plasma was found to be high. In 2 prostate cancer xenograft models (PC-3 and LNCaP), 18 F-BAY 86-4367 showed more specific and effective GRPr-based targeting in vivo than the benchmark radiotracers 18 F-fluoroethylcholine and 18 F-FDG. In addition, rapid tumor targeting and fast renal excretion (;70%) and hepatobiliary excretion (;10%) were identified in both xenograft models. Furthermore, PET studies provided clear and specific visualization of PC-3 tumors in mice. Conclusion: Favorable preclinical data showing specific and effective tumor targeting by 18 F-BAY 86-4367 suggest that a clinical trial be undertaken to test its diagnostic utility in PET for prostate carcinoma patients.

18F-AmBF3-MJ9: A novel radiofluorinated bombesin derivative for prostate cancer imaging

“…Other methods have also been used for radiofluorination of bombesin derivatives, notably by using N-succinimidyl-4-18 F-fluorobenzoate, 3-cyano-4-18 F-fluoro-benzoyl derivatives or fluoropyridine prosthetic groups, with variable success. [37][38][39][40] All of these methods required one or two HPLC purification steps, with lengthy radiolabeling procedures. Considering the widespread availability of 18 F, and the straightforward labeling technique using the 18 F-19 F isotope exchange reaction, 18 FAmBF 3 -MJ9 is a promising probe for non-invasive imaging of GRPR in humans.…”

GPCRs and cancer

“…In this regard, it was demonstrated that the anti-tumor activity of GrP antagonists involves different mechanisms as the reduction of EGFR and Her2 levels, the alteration of MAPK, PKC, pAkt, and COX-2 signaling, the attenuation of c-fos and c-jun expression, the modulation of wild-type and mutated forms of p53 along with an alteration of Bcl-2/BAX ratio, the inhibition of vascular endothelial growth factor (VEGF) [47] . Radiolabeled GrP analogues represent another chance in targeting GrP receptors, thus they are currently considered promising radiopharmaceuticals for detection and treatment of different types of tumors [48,49] .…”

Dosimetry and First Clinical Evaluation of the New 18F-Radiolabeled Bombesin Analogue BAY 864367 in Patients with Prostate Cancer

“…However, they showed only limited success, probably because of their limited metabolic stability. Recently, the 18 F-labeled BAY 864367 was identified as a potent synthetic GRPr antagonist, and its preclinical evaluation showed specific and effective GRPr targeting in PC-3 tumor-bearing mice, with high tumor uptake, excellent tumor-to-background ratios, and, importantly, excellent metabolic stability (11). To further investigate this promising tracer, an exploratory clinical trial was performed.…”

“…The poor performance of the most commonly used tracer in cancer, 18 F-labeled glucose ( 18 F-FDG), for the detection of PCa is due to the relatively slow growth of well-differentiated PCa and consequently low glucose metabolism (3,4). This drawback has led to the development of other PET tracers such as 11 C-choline and 18 F-choline, which have been reported to be potentially useful for the detection of PCa lesions and are in routine clinical use (5)(6)(7). However, the fact that radiolabeled choline analogues cannot differentiate between benign hyperplastic prostate cells and malignant carcinoma cells may limit their diagnostic value.…”

“…BAY 864367 (3-cyano-4-18 F-fluorobenzoyl-Ala(SO 3 H)-Ala(SO 3 H)-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH 2 ) (Fig. 1) has been identified as a potent synthetic GRPr antagonist that can be directly radiolabeled with 18 F and has clearly visualized human PCa (PC-3) xenografts in mice (11). The aim of this first-in-man study was to demonstrate the feasibility, safety, and tolerability, as well as provide dosimetric data and get first hints on the diagnostic value, of the PET tracer BAY 864367 in patients with primary and recurrent PCa.…”