Bombesin Receptor-Mediated Imaging and Cytotoxicity: Review and Current Status

Abstract

The three mammalian bombesin (Bn) receptors (gastrin-releasing peptide [GRP] receptor, neuromedin B [NMB] receptor, BRS-3) are one of the classes of G protein-coupled receptors that are most frequently over-express/ectopically expressed by common, important malignancies. Because of the clinical success of somatostatin receptor-mediated imaging and cytotoxicity with neuroendocrine tumors, there is now increasing interest in pursuing a similar approach with Bn receptors. In the last few years then have been more than 200 studies in this area. In the present paper, the in vitro and in vivo results, as well as results of human studies from many of these studies are reviewed and the current state of Bn receptor-mediated imaging or cytotoxicity is discussed. Both Bn receptor-mediated imaging studies as well as Bn receptor-mediated tumoral cytotoxic studies using radioactive and non-radioactive Bn-based ligands are covered. Keywordsbombesin; gastrin-releasing peptide; neuromedin B; BRS-3; receptor-mediated imaging; tumor cytotoxicity; DOTA; DTPA; NOTA I. Bombesin (Bn) receptor family-General (Table 1,2)The mammalian Bn receptor family is receiving increased attention as a means of localizing tumors or other disease processes by receptor-mediated imaging or for receptor-mediated cytotoxicity of tumors [1][2][3][4][5]. This family got its unusual name, because the original members of this peptide family were isolated from various frog skins and were named after the frog they were isolated from, with the original amidated tetradecapeptide isolated from the European frog, Bombina bombina in 1970 [6][7][8] (Table 2). Subsequently, a large number of related peptides were isolated which were divided into three groups: the Bn-related peptides with a COOH terminal, Gly-His-Leu-Met-NH 2 , the ranatesin-litorin group with a COOH terminus of Gly-His-Phe-Met-NH 2 and the phyllolitorin group with a COOH terminus ending in Gly-Ser-Phe/Leu-Met-NH 2 (Table 2) [6][7][8]. Subsequently two mammalian equivalent peptides were isolated, gastrin-releasing peptide (GRP), a 27 amino Corresponding author: Dr R.T. Jensen, Building 10, Room 9C-103, National Institutes of Health, Bethesda, MD 20892, Phone-301-496-4201, Fax-301-402-0600, robertj@bdg10.niddk.nih.gov. * Both authors contributed equally to this work Conflict of Interest: None NIH Public Access Author ManuscriptCurr Drug Deliv. Author manuscript; available in PMC 2012 January 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript acid peptide which shares the same seven COOH terminal amino acids with Bn (Table 2) [9] and the decapeptide, neuromedin B (NMB) (Tables 1,2) which shares 6 of the 7 COOH terminal amino acids with litorin (Table 2) [10]. Each of these peptides is widely distributed in both the central nervous system (CNS) and peripheral tissues, especially in the gastrointestinal (GI) tract [8]. Numerous studies demonstrate these two peptides are involved in a wide range of physiological and pathophysiological processes which include: in the CNS...

Preclinical Comparison of Al18F- and 68Ga-Labeled Gastrin-Releasing Peptide Receptor Antagonists for PET Imaging of Prostate Cancer

“…A variety of radiolabeled BBN analogs have been developed for targeting GRPR-positive tumors and were evaluated in preclinical and clinical studies (5). Several recent reports have shown that GRPR antagonists show properties superior to GRPR agonists, affording higher tumor uptake and lower accumulation in physiologic GRPR-positive nontarget tissues (11,12).…”

The future of nuclear medicine imaging of neuroendocrine tumors: on a clear day one might see forever…

“…In vitro usage to identify prostate cancer indicates positive identification in 60-100 % [35][36][37][38][39]. Similarly, GRP and BB 3 receptors have been identified in 7/10 and 2/10 gastrinomas, respectively, NMB receptors have been found in 11/27 ileal, while BB3 receptors were the predominant receptors described in 10/29 bronchial NETs [36].…”

“…More than 40 different bombesin analogs, agonists and antagonists labeled with 99m Tc or with 68 Ga have been evaluated in vitro. They comprise an additional potential class of radiopharmaceuticals for NET imaging [37].…”

99mTc Radiotracers Based on Human GRP(18-27): Synthesis and Comparative Evaluation

“…Anal ogs of the frog tetradecapeptide bombesin (BBN) have been exploited as molecular vehicles to direct diagnostic and therapeutic radionuclides to human primary and metastatic cancer (1)(2)(3). This approach relies on the high-density expression of gastrin-releasing peptide receptors (GRPRs) in many frequently occurring human cancers, such as prostate cancer, mammary carcinoma, or small cell lung cancer, as opposed to their lower abundance or lack of expression in surrounding healthy tissue (4)(5)(6)(7)(8)(9).…”

“…These analogs indeed showed high affinity for the human GRPR, rapid internalization into human prostate cancer PC-3 cells, and effective targeting of PC-3 tumors xenografted in immunosuppressed mice, whereas their excretion from the body of mice was found to be dependent on peptide length or hydrophilicity of spacers introduced between metal-chelate and peptide chain (11). Urged by the lack of studies on radioligands based on human homologs of amphibian BBN, we have recently expanded our research activities toward human peptide sequences, such as the 27-mer GRP and its Cterminal decapeptide fragment GRP (18)(19)(20)(21)(22)(23)(24)(25)(26)(27), otherwise referred to as neuromedin C (3,12). Hence, we have recently introduced 99m Tc-demomedin C, formed by coupling an acyclic tetraamine chelator to the primary amine of Gly 18 of GRP (18)(19)(20)(21)(22)(23)(24)(25)(26)(27) to allow for labeling with 99m Tc (13).…”