Synthesis and biologic evaluation of 64Cu-labeled rhenium-cyclized alpha-MSH peptide analog using a cross-bridged cyclam chelator.

Abstract

UNLABELLED:

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).

CONCLUSION:

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.

• Authors: Lihui Wei, Clayton Butcher, Yubin Miao, Fabio Gallazzi, Thomas P Quinn, Michael J Welch, Jason S Lewis
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 48 Issue 1 Pg. 64-72 (Jan 2007) ISSN: 0161-5505 [Print] United States
• PMID: 17204700 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chelating Agents
• Copper Radioisotopes
• Heterocyclic Compounds
• Organometallic Compounds
• Peptides
• Peptides, Cyclic
• Radiopharmaceuticals
• copper 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane-ReCCMSH(Arg(11))
• cyclam
• alpha-MSH
• Rhenium
• Trifluoroacetic Acid

Topics

• Animals
• Chelating Agents (chemistry)
• Copper Radioisotopes (chemistry)
• Female
• Heterocyclic Compounds (chemistry)
• Melanoma, Experimental (diagnostic imaging)
• Mice
• Mice, Inbred C57BL
• Neoplasm Transplantation
• Organometallic Compounds (chemical synthesis)
• Peptides (chemistry)
• Peptides, Cyclic (chemical synthesis)
• Positron-Emission Tomography (instrumentation, methods)
• Radiopharmaceuticals (chemical synthesis)
• Rhenium (chemistry)
• Trifluoroacetic Acid (pharmacology)
• alpha-MSH (chemistry)