Gastrin-releasing peptide (GRP) analogues for cancer imaging

Small neuropeptides, labeled with gamma- and/or beta-emitting radionuclides, are currently being investigated for their ability to bind to cell-surface receptors, overexpressed in a wide variety of malignant tissues being, thus, potentially useful for radionuclide detection and/or therapy for tumors. Particular attention has been focused on the amphibian peptide, bombesin (BN), and the molecularly related gastrin-releasing peptide (GRP). These peptides act as neurotransmitters and endocrine cancer cell-growth factors on normal tissues as well as on neoplastic cells of various origin. In recent investigations, modification of the native peptide structure has been attempted in order to obtain derivatives, which might easily be labeled with radionuclides. Thus, iodinated (I-125) BN derivatives, as well as Indium (In-111) labeled BN analogs are currently being investigated, presenting satisfactory tumor localization. Also, some new BN analogs containing a 6-carbon linker have been prepared and labeled with Rhenium-188, resulting in positive in vitro binding to prostate cancer cells. More recent studies refer to the Technetium-99m labeling of BN, performed either directly, after attaching proper technetium-chelating groups onto the BN sequence, or indirectly, by coupling BN to a preformed 99mTc-tagging ligand. Both types of conjugates were found to have a high in vitro affinity for cells with BN receptors, also presenting satisfactory in vivo uptake in experimental tumor models. Pilot clinical studies of a new BN-derived, 99mTc-labeled pentadecapeptide indicated significant uptake by breast cancer and invaded lymph nodes, as well as by prostate cancer, small-cell lung carcinoma, gastro-entero-pancreatic tumors, and others, Further studies of this new GRP derivative, as well as of other new BN-like peptides, are intensively performed internationally today.