Molecular Imaging of Gastrin-Releasing Peptide Receptor-Positive Tumors in Mice Using⁶⁴Cu- and⁸⁶Y-DOTA−(Pro¹,Tyr⁴)-Bombesin(1−14)

Abstract

Bombesin is a tetradecapeptide neurohormone that binds to gastrin-releasing peptide receptors (GRPR). GRPRs have been found in a variety of cancers including invasive breast and prostate tumors. The peptide MP2346 (DOTA-(Pro(1),Tyr(4))-bombesin(1-14)) was designed to bind to these GRP receptors. This study was undertaken to evaluate radiolabeled MP2346 as a positron emission tomography (PET) imaging agent. MP2346 was radiolabeled, in high radiochemical purity, with the positron-emitting nuclides (64)Cu (t(1/2) = 12.7 h, beta+ = 19.3%, E(avg) = 278 keV) and (86)Y (t(1/2) = 14.7 h, beta+ = 33%, E(avg) = 664 keV). (64)Cu-MP2346 and (86)Y-MP2346 were studied in vitro for cellular internalization by GRPR-expressing PC-3 (human prostate adenocarcinoma) cells. Both (64)Cu- and (86)Y-MP2346 were studied in vivo for tissue distribution in nude mice with PC-3 tumors. Biodistribution in PC3 tumor-bearing mice demonstrated higher tumor uptake, but lower liver retention, in animals injected with (86)Y-MP2346 compared to (64)Cu-MP2346. Receptor-mediated uptake was confirmed by a significant reduction in uptake in the PC-3 tumor and other receptor-rich tissues by coinjection of a blockade. Small animal PET/CT imaging was carried out in mice bearing PC-3 tumors and rats bearing AR42J tumors. It was possible to delineate PC-3 tumors in vivo with (64)Cu-MP2346, but superior (86)Y-MP2346-PET images were obtained due to lower uptake in clearance organs and lower background activity. The (86)Y analogue demonstrated excellent PET image quality in models of prostate cancer for the delineation of the GRPR-rich tumors and warrants further investigation.

Small-Animal PET of Tumors with 64Cu-Labeled RGD-Bombesin Heterodimer

“…The 64 Cu-DOTA conjugates usually exhibit a high accumulation of liver radioactivity (17,24) because of the dissociation of 64 Cu in vivo from DOTA, followed by metabolism and transchelation to other proteins (16,25,26). NOTA is most commonly used for 68 Ga (half-life, 68 min) labeling because the rapid reaction kinetics of NOTA match the short half-life of 68 Ga. NOTA was also reported to be labeled with 64 Cu, with reduced liver accumulation (15).…”

PET of Tumors Expressing Gastrin-Releasing Peptide Receptor with an 18F-Labeled Bombesin Analog

“…In previous studies in PC-3-bearing mice, 67 Ga-PESIN, 177 Lu-AMBA, and 99m Tc-demobesin-1 showed tumor uptake of 14.8, 6.4, and 16.2 %ID/g, respectively (9,(25)(26)(27)(28). Variation in amounts of peptides, mouse strain (species, sex, and weight), tumor cells (passage number, culture conditions) used, tumor size, and vascularization of the tumor may all be factors that affect tumor uptake and tumor-to-non-tumor ratios.…”

“…The uptake of the 64 Cu-labeled NOTA-8-Aoc-BBN (7)(8)(9)(10)(11)(12)(13)(14) conjugate in PC-3-bearing mice (3.59 6 0.70 % ID/g, 1 h after injection) was similar to the tumor uptake for our radiolabeled compounds (2.15-1.24.%ID/g, 1 h after injection) (16). However, Lears et al recently reported in this tumor model a tumor uptake as high as 13.0 %ID/g at 1 h after injection using 64 Cu-labeled SarAr-SA-Aoc-BBN(7-14) (23).…”

“…Therefore, the N-terminus of BBN is usually modified for labeling the analogs with radioisotopes. A variety of BBN analogs has been developed and labeled with various radionuclides, such as 99m Tc and 111 In, for SPECT (8) and 64 Cu, 68 Ga, or 86 Y for PET (9,10). 18 F is the most widely used radionuclide in PET.…”

Molecular Imaging of Breast Cancer Tissue via Site-Directed Radiopharmaceuticals

“…It has been shown that the GRPR is over-expressed on the surface of T-47D breast carcinoma cells while being absent from normal breast tissues (Giacchetti et al, 1990). This receptor has served as a target for a number of diagnostic and therapeutic strategies Garrison et al, 2007;Parry et al, 2007;Biddlecombe et al, 2007;Guojun et al, 2008;Zhou et al, 2003;Ma et al, 2007). T-47D xenografts in mice have been used in preclinical investigations of a variety of diagnostic modalities (Giblin et al, 2006;Aliaga et al, 2004).…”