68Ga-Labeled Bombesin Analogs for Receptor-Mediated Imaging

Abstract

Targeted receptor-mediated imaging techniques have become crucial tools in present targeted diagnosis and radiotherapy as they provide accurate and specific diagnosis of disease information. Peptide-based pharmaceuticals are gaining popularity, and there has been vast interest in developing (68)Ga-labeled bombesin (Bn) analogs. The gastrin-releasing peptide (GRP) family and its Bn analog have been implicated in the biology of several human cancers. The three bombesin receptors GRP, NMB, and BRS-3 receptor are most frequently ectopically expressed by common, important malignancies. The low expression of Bn/GRP receptors in normal tissue and relatively high expression in a variety of human tumors can be of biological importance and form a molecular basis for Bn/GRP receptor-mediated imaging. To develop a Bn-like peptide with favorable tumor targeting and pharmacokinetic characteristics for possible clinical use, several modifications in the Bn-like peptides, such as the use of a variety of chelating agents, i.e., acyclic and macrocyclic agents with different spacer groups and with different metal ions (gallium), have been performed in recent years without significant disturbance of the vital binding scaffold. The favorable physical properties of (68)Ga, i.e., short half-life, and the fast localization of small peptides make this an ideal combination to study receptor-mediated imaging in patients.

Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment

“…A recent prospective, double-blind study(NETTER-1) reported in preliminary form[51], in 230 patients (randomized 1:1) with advanced, inoperable, progressive, small intestinal, metastatic ileal carcinoid tumors, demonstrates for the first time, that using a 177 Lutetium-labeled-somatostatin-analogue, results in a highly significant extension of progressive-free survival compared to patients not treated with the 177 Lutetium-labeled-somatostatin analogue(p<0.0001) and likely extension of survival(23 vs 67 deaths), with acceptable toxicity. Unfortunately, most common neoplasms do not overexpress somatostatin-receptors, however, many overexpress BnR’s[1,23], which has led to markedly increased interest in using a similar approach using Bn-analogues to both image primary tumor location and extent of these tumors,as well as to target them with cytotoxic-agents[12,13,16•,52]. …”

“…These include reviews of general advances in all these aspects[2••,3]; the role of BRS-3 in obesity and diabetes[5]; the role of BnR’s in feeding disorders[2••,8]; pruritis[2••,9]; CNS function/disorders including memory, stress[2••,10]; lung diseases[2••]; inflammatory disorders[2••,11]; the signaling especially in cancer[2••,7] and the development of BnR-ligands as possible imaging modalities[2••,12,13]. In the present paper the possible role of BnRs in neoplastic processes will be concentrated on with a view to the use of their overexpression/growth effects by many human-cancers as a potential novel target for treatment.…”

Bench to bedside molecular functional imaging in translational cancer medicine: to image or to imagine?

“…163e165 Radiolabelled somatostatin analogues that have been used with SPECT include 99m Tc, 123 I, and 111 In, and with PET include 68 Ga and 64 Cu. SSTR-directed radionuclide therapies have shown 80% disease stabilisation rates with better response rates from newer 90 Yand 177 Lu-labelled SSTR therapies 163e165 (Fig 10).…”

“…174,175 PET tracers, such as 64 Cu-DOTA-[Lys3]-BN and 68 Ga-labelled-BN, have been tested for safety and efficacy in prostate and pancreatic cancer xenografts models. 176,177 The HER-2/neu receptor is a member of the EGF family and is amplified in many cancers and is both a prognostic as well as a therapeutic marker. 178,179 Recently developed, novel two-component gadolinium-based MRI contrast agents, i.e., avidin-Gd conjugated with DTPA for HER-2/neu receptor imaging and anti-HER-2/neu antibody herceptin labelled with the 68 Ga for PET imaging in breast cancer xenografts have been used to study the degradation of HER-2/neu in response to a novel anti-cancer drug Hsp90-inhibitor 17-allylaminogeldanamycin (17-AAG).…”

Current Trends in Using PET Radiopharmaceuticals for Dia gnostics in Oncology

“…Jeho širšímu rozšíření zatím brá-nila suboptimální dostupnost spojená s výše zmíněnými problémy. Označitel-ných a využitelných markerů je nicméně velké množství, v současné době prová-děné studie s PSMA (prostate-specifi c membrane antigen) [68][69][70] či bombesinem [71] (tumorový marker např. pro malobuněčný karcinom plic, neuroblastomy či nádory žaludku) označenými gal liem jsou pouhými prvními příklady dynamicky se rozvíjejícího nového pole vysoce specifi ckých PET radiofarmak.…”