Synthesis and biologic evaluation of 64Cu-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 (64)Cu-DOTA-ReCCMSH(Arg(11)) (DOTA is 1,4,7,10-tetraazacyclododecane-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, (64)Cu-DOTA-ReCCMSH(Arg(11)) demonstrated high background in nontarget tissues due to the in vivo instability of the Cu-DOTA 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 (64)Cu 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 (64)Cu-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 (64)Cu- and (86)Y-labeled DOTA-ReCCMSH(Arg(11)). Nontarget organ concentration for (64)Cu-CBTE2A-ReCCMSH(Arg(11)) was considerably lower than that of the (64)Cu-DOTA analog, resulting in significantly higher tumor-to-nontarget tissue ratios. Compared with (86)Y-DOTA-ReCCMSH(Arg(11)), (64)Cu-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).


CONCLUSIONS
Our data suggest the superior stability of the (64)Cu-CBTE2A moiety compared with (64)Cu-DOTA, making (64)Cu-CBTE2A-ReCCMSH(Arg(11)) an ideal candidate for the PET of malignant melanoma.
Wei
Lihui
L
Division of Radiological Sciences, Mallinckrodt Institute of Radiology and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Butcher
Clayton
C
Miao
Yubin
Y
Gallazzi
Fabio
F
Quinn
Thomas P
TP
Welch
Michael J
MJ
Lewis
Jason S
JS
D000818:Animals; D002614:Chelating Agents / Q000737:chemistry; D003301:Copper Radioisotopes / Q000737:chemistry; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry; D008546:Melanoma, Experimental / Q000000981:diagnostic imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009942:Organometallic Compounds / Q000138:chemical synthesis*; D010455:Peptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis*; D049268:Positron-Emission Tomography / Q000295:instrumentation* / Q000379:methods; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D012211:Rhenium / Q000737:chemistry; D014269:Trifluoroacetic Acid / Q000494:pharmacology; D000521:alpha-MSH / Q000737:chemistry
D002614:Chelating Agents; D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D010455:Peptides; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; C517419:copper 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane-ReCCMSH(Arg(11)); C024560:cyclam; D000521:alpha-MSH; D012211:Rhenium; D014269:Trifluoroacetic Acid