Potent Bombesin-like Peptides for GRP-Receptor Targeting of Tumors with ^99mTc:  A Preclinical Study

Abstract

Four open chain tetraamine-functionalized bombesin (BB) analogues were synthesized [parent tetradecapeptide-based Demobesin 3 and 4 and BB(7-14)-based Demobesin 5 and 6]. Labeling with (99m)Tc afforded high-purity and high specific activity radiotracers. Peptides showed high affinity for the human GRP-R (GRP-R = gastrin releasing peptide receptor) expressed in PC-3 cells. In human tumors preferentially expressing single bombesin receptor subtypes, they showed high affinity for the GRP-R, less affinity for the NMB-R (NMB-R = neuromedin B receptor) and no affinity for the orphan BB(3)-R (bombesin subtype 3 receptor). [(99m)Tc]Demobesin 3-6 efficiently internalized in a time- and dose-dependent manner in PC-3 cells and showed a high and specific uptake in human PC-3 xenografts and the pancreas of nude mice. [(99m)Tc]Demobesin 3 and 4 were rapidly excreted via the kidneys while the truncated analogues were predominantly processed by the hepatobiliary system. Patient studies are scheduled for validating the suitability of [(99m)Tc]Demobesin 3 and 4 in the GRP-R-targeted imaging of tumors.

Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin

“…Besides high uptake in the pancreas, uptake was also observed in the kidneys and lungs. Moreover, SPECT images after injection of 99m Tc-labelled demobesin 3, specifically accumulating in the pancreas [27], correlated with the pancreatic uptake of 111 In-labelled exendin (ESM Fig. 1), confirming that the VOI used for quantification of BCM is indeed located in the pancreas.…”

Synthesis and Characterization of a High-Affinity NOTA-Conjugated Bombesin Antagonist for GRPR-Targeted Tumor Imaging

“…Bombesin analog NOTA-PEG 2 -[D-Phe 6 ,Sta 13 ,Leu 14 ]bombesin [6][7][8][9][10][11][12][13][14] (further denoted as NOTA-P2-RM26, see Chart) was synthesized by standard manual solid-phase peptide synthesis 17 as described in Supplementary material 1.…”

“…5 BN that has two mammalian homologs, neuromedin B (NMB) 6 and GRP, 7 is a linear tetradecapeptide and has high affinity to GRPRs. BN-based tracer agonists have been extensively investigated in preclinical 8,9 and clinical studies. 10,11 All demonstrated high binding affinity to GRPRs and good radioligand internalization properties which are essential factors for optimal imaging.…”

Gastrin-releasing peptide (GRP) induces angiogenesis and the specific GRP blocker 77427 inhibits tumor growth in vitro and in vivo

“…Inhibitors of GRP have shown promising antitumor effects in animal models (Kiaris et al, 1999;Moody et al, 2003a, b;Nock et al, 2005) and in the clinic (Chaudhry et al, 1999). We have recently found a new class of GRP blockers that bind to the peptide rather than to the receptor (Martı´nez et al, 2004a).…”