MicroPET Imaging of Breast Cancer Using Radiolabeled Bombesin Analogs Targeting the Gastrin-releasing Peptide Receptor

Abstract

Mammography is a well-established method for detecting primary breast cancer; however, it has some limitations that may be overcome using nuclear imaging methods. Current radiopharmaceuticals have limited sensitivity for detecting small primary lesions and it has been suggested that novel radiopharmaceuticals are necessary for detection of primary breast cancer, as well as for detecting metastases and recurrence, or for monitoring therapy. The gastrin-releasing peptide receptor (GRPR) is a seven-transmembrane G-protein coupled receptor that is overexpressed on primary breast cancer and lymph node metastases. Bombesin (BN) is a tetradecapeptide that binds with high affinity to GRPR and can be radiolabeled with the positron-emitter, copper-64 ((64)Cu) for imaging with positron-emission tomography (PET). The goal of this study was to evaluate BN analogs that could be radiolabeled with (64)Cu for PET imaging of breast cancer. A series of BN analogs containing 4, 5, 6, 8, and 12- carbon linkers were evaluated with regard to their binding and internalization into T-47D human breast cancer cells. The (64)Cu-labeled analogs were then evaluated in mice bearing T-47D xenografts by tissue biodistribution and microPET imaging. These studies showed that all of the analogs had IC(50) values <100 nM and were all internalized into T-47D cells. Biodistribution studies showed that the BN analog with the 8-carbon linker not only had the highest tumor uptake but also had high normal tissue uptake in the liver. The analogs containing the 6- or 8-carbon linkers demonstrated good tumor uptake as determined by microPET imaging. Overall, this study shows the feasibility of using positron-labeled BN analogs for PET detection of GRPR-expressing breast cancer.

Bombesin-related peptides and their receptors: recent advances in their role in physiology and disease states

“…Therefore the development of labeled Bn analogues for imaging or targeted cytotoxicity is a very active area of investigation at present. Numerous radiolabeled [ 111 Indium, 68 Gallium, 177 Lutetium, 64 Copper, 86 Yttrium, 18 F, 99m Tc] GRP analogues with enhanced stability that bind with high affinity to BB 2 -receptors are reported, as well as there ability to image various human tumors in vivo using gamma detectors or PET imaging [10,[69][70][71][72][73][74][75][76][77]. In some preliminary studies in humans, tumors were imaged in the majority of patients, and in some cases, tumors were detected using radiolabeled Bn analogues that were not seen on other commonly used imaging modalities [75,[78][79][80].…”

Evaluation of a 1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetraacetic Acid–Conjugated Bombesin-Based Radioantagonist for the Labeling with Single-Photon Emission Computed Tomography, Positron Emission Tomography, and Therapeutic Radionuclides

“…They show antitumor activity in murine and human tumors (14)(15)(16). Moreover, the development of radiolabeled peptides for imaging and targeted radionuclide therapy has been advanced in recent years (17)(18)(19)(20)(21)(22)(23)(24). Clinical studies with […”

Gastrin-releasing peptide promotes the growth of HepG2 cells via EGFR-independent ERK1/2 activation

“…At present, several GRP analogues and GRPR antagonists are in preclinical trials for tumor imaging and anticancer therapy (8)(9)(10)(11)(12)(13)(14). Although it has been reported that GRP played a role in hepatocarcinogenesis in rat (19), no data are currently available confirming the contribution of GRP to human HCC.…”

“…In particular, GRP serves as a potent mitogen for various types of tumor including small cell lung, pancreatic, prostate, renal, breast and colon cancers (1)(2)(3)(4)(5)(6)(7). Furthermore, treatment with GRP antibody was found to lead to significant anti-proliferative effects, indicating that GRP is an autocrine growth factor and GRPR may be a drug target for tumor imaging and anti-tumor therapy (8)(9)(10)(11)(12)(13)(14).…”