Radiolabeled Bombesin Analogs

Abstract

The gastrin-releasing peptide receptor (GRPR) is expressed in high numbers in a variety of human tumors, including the frequently occurring prostate and breast cancers, and therefore provides the rationale for directing diagnostic or therapeutic radionuclides on cancer lesions after administration of anti-GRPR peptide analogs. This concept has been initially explored with analogs of the frog 14-peptide bombesin, suitably modified at the N-terminus with a number of radiometal chelates. Radiotracers that were selected for clinical testing revealed inherent problems associated with these GRPR agonists, related to low metabolic stability, unfavorable abdominal accumulation, and adverse effects. A shift toward GRPR antagonists soon followed, with safer analogs becoming available, whereby, metabolic stability and background clearance issues were gradually improved. Clinical testing of three main major antagonist types led to promising outcomes, but at the same time brought to light several limitations of this concept, partly related to the variation of GRPR expression levels across cancer types, stages, previous treatments, and other factors. Currently, these parameters are being rigorously addressed by cell biologists, chemists, nuclear medicine physicians, and other discipline practitioners in a common effort to make available more effective and safe state-of-the-art molecular tools to combat GRPR-positive tumors. In the present review, we present the background, current status, and future perspectives of this endeavor.

Keywords: cancer theranostics; gastrin-releasing peptide receptor; radiolabeled bombesin.

Figure 1

Amino acid sequence of frog BBN and the respective GRP, NMC, and NMB peptides, native in humans; conserved residues are indicated by red color.

Figure 2

After binding, agonists activate the GRPR on the target-cell membrane, whereas antagonists do not. Antagonists compete with agonists for GRPR binding, and thereby (partially) ban the agonist-induced activation of the GRPR.

Figure 3

Major BBN- and GRP-based motifs used in the GRPR antagonist design.

Figure 4

Patient with PC, post radical prostatovesiculectomy with pelvic lymphadenectomy, IMRT, and androgen deprivation therapy (PSA on date of scan, 21.77 ng/mL). [⁶⁸Ga]Ga-NeoBOMB1 PET/CT: (A) PET MIP; (B) serial PET transverse; (C) corresponding CT transverse; (D) fusion PET/CT images. Multiple mediastinal, abdominal, paraoesophageal and pelvic lymph node metastatses (arrows and crossbars). This research was originally published in JNM 2017 [34].

Figure 5

(a) The radiolabeled peptide conjugate (based on a GRPR agonist or antagonist) after entering the blood (top) is attacked by NEP (indicated by the two descending green arrows) and is degraded. As a result, only a few of the initial molecules arrive intact at the tumor cells and interact with the GRPR (orange receptors) located at the cell membrane (bottom); (b) following co-administration of a NEP inhibitor, the degrading action of NEP is suspended, and thus the number of intact molecules arriving at the tumor and binding to GRPR sites is higher, leading to higher tumor uptake.

Figure 6

The pretargeting concept for safe and effective GRPR-mediated radionuclide therapy: (a) The targeting vector adapted with a click moiety is injected first. It binds to the GRPR on the cells of the pancreas and on GRPR-expressing tumor cells. When the targeting vector is (mostly) cleared from the pancreas but still present on the tumor cells, a radiolabeled small molecule containing a complementary click element is injected. This radiolabeled small molecule couples the targeting vector still present on the tumor cells, hereby, specifically delivering radioactivity to these cells; (b) graph depicting uptake of the targeting vector and radioactivity/radiation dose to the pancreas and tumor using the pretargeting strategy.

Figure 7

Maximum intensity projection [⁶⁸Ga]Ga-RM2 and [⁶⁸Ga]Ga-PSMA-11 images of the 7 enrolled prostate cancer patients. This research was originally published in JNM 2016 [103].