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The BB2 receptor subtype, of the bombesin family of receptors, has been shown to be highly overexpressed in a variety of human tumors, including prostate cancer. Bombesin (BBN), a 14-amino acid peptide, has been shown to target the BB2 receptor with high affinity. 64 Cu (half-life 5 12.7 h, b 1 : 18%, E b1max 5 653 keV; b 2 : 37%, E b2max 5 578 keV) is a radioisotope that has clinical potential for application in both diagnostic imaging and radionuclide therapy. Recently, new chelation systems such as 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A) have been reported to significantly stabilize the 64 Cu radiometal in vivo. The increased stability of the 64 Cu-CB-TE2A chelate complex has been shown to significantly reduce nontarget retention compared with tetraazamacrocycles such as 1,4,7,10-tetraazacyclodoadecane-N,N9,N99,N999-tetraacetic acid (DOTA). The aim of this study was to determine whether the CB-TE2A chelation system could significantly improve the in vivo stability of 64 Cu bombesin analogs. The study directly compares 64 Cu bombesin analogs using the CB-TE2A and DOTA chelation systems in a prostate cancer xenograft SCID (severely compromised immunodeficient) mouse model. Methods: The CB-TE2A-8-AOC-BBN(7-14)NH 2 and DOTA-8-AOC-BBN(7-14) NH 2 conjugates were synthesized and radiolabeled with 64 Cu. The receptor-binding affinity and internalization profile of each metallated conjugate was evaluated using PC-3 cells. Pharmacokinetic and small-animal PET/CT studies were performed using female SCID mice bearing PC-3 xenografts. Results: In vivo BB2 receptor targeting was confirmed by tumor uptake values of 6.95 6 2.27 and 4.95 6 0.91 %ID/g (percentage injected dose per gram) at the 15-min time point for the 64 Cu-CB-TE2A and 64 Cu-DOTA radioconjugates, respectively. At the 24-h time point, liver uptake was substantially reduced for the 64 Cu-CB-TE2A radioconjugate (0.21 6 0.06 %ID/g) compared with the 64 Cu-DOTA radioconjugate (7.80 6 1.51 %ID/g). The 64 Cu-CB-TE2A-8-AOC-BBN(7-14)NH 2 radioconjugate demonstrated significant clearance, 98.60 6 0.28 %ID, from the mouse at 24 h after injection. In contrast, only 67.84 6 5.43 %ID of the 64 Cu activity was excreted using the 64 Cu-DOTA-8-AOC-BBN(7-14)NH 2 radioconjugate because of nontarget retention. Conclusion: The pharmacokinetic and small-animal PET/CT studies demonstrate significantly improved nontarget tissue clearance for the 64 Cu-CB-TE2A8-AOC-BBN(7-14)NH 2 . This is attributed to the improved in vivo stability of the 64 Cu-CB-TE2A chelate complex as compared with the 64 Cu-DOTA chelate complex. The bombesin family of receptors-in particular, the BB2 receptor-has received a great deal of attention as a potential target for target-directed radiopharmaceuticals due to the high densities of these receptors on a variety of human tumors (1-3). The BB2 receptor subtype has been the most thoroughly studied receptor of the bombesin family and has been shown to be overexpressed in prostate, breast, small cell lung, and pancreatic cancers. ...