Synthesis And Biologic Evaluation Of Cu-64-Labeled Rhenium-Cyclized Alpha-Msh Peptide Analog Using A Cross-Bridged Cyclam Chelator

Early detection of cutaneous melanoma is essential, as prognosis with metastatic melanoma is poor. Previous studies showed that Cu-64-DOTA-ReCCMSH(Arg(11)) (DOTA is 1,4,7,10-tetraaza-cyclododecane-N,N',N",N'''-tetraacetic acid), a cyclic analog of alpha-melanocyte-stimulating hormone (alpha-MSH), has the potential for the detection of malignant melanoma using PET. However, Cu-64-DOTA-ReCCMSH(Arg(11)) demonstrated high background in nontarget tissues due to the in vivo instability of the CuDOTA moiety. CBTE2A (CBTE2A is 4,11-bis(carboxymethyl)-1,4,8,11 -tetraazabicyclo[6.6.2]hexadecane) has been shown to be a more stable copper chelate with improved in vivo stability, resulting in an improvement in clearance from nontarget tissues. The goal of this study was to conjugate CBTE2A to the alpha-MSH targeting ReCCMSH(Arg(11)) peptide for labeling to Cu-64 and to investigate whether the increased metal-chelate stability with CBTE2A would improve imaging quality. Methods: The recyclized peptide CBTE2A-ReCCMSH(Arg(11)) was synthesized using a solid-phase peptide synthesizer followed by rhenium cyclization. In vivo characteristics of Cu-64-CBTE2A-ReCCMSH(Arg(11)) were examined with small-animal PET and acute biodistribution studies in B16/F1 tumor-bearing mice. Results: Biodistribution studies showed high and rapid receptor-mediated tumor uptake with values similar to those reported for Cu-64- and Y-86-labeled DOTA-ReCCMSH(Arg(11)). Nontarget organ concentration for Cu-64-CBTE2A-ReCCMSH(Arg11) was considerably lower than that of the 64Cu-DOTA analog, resulting in significantly higher tumor-to-nontarget tissue ratios. Compared with Y-86-DOTAReCCMSH(Arg(11)), Cu-64-CBTE2A-ReCCMSH(Arg(11)) demonstrated increased tumor retention and kidney clearance. Small-animal PET images showed that the tumor could be clearly visualized at all time points (0.5-24 h). Conclusion: Our data suggest the superior stability of the Cu-64-CBTE2A moiety compared with 64Cu-DOTA, making Cu-64-CBTE2A-ReCCMSH(Arg(11)) an ideal candidate for the PET of malignant melanoma.