Early detection of melanoma is essential, since a patient's prognosis with metastatic melanoma is poor. Previous studies showed that (111)In-DOTA-ReCCMSH(Arg(11)), a cyclic analogue of alpha-melanocyte stimulating hormone (alpha-MSH), exhibited high tumor concentration and rapid clearance from nontarget tissue. The goal of this current study was to label DOTA-ReCCMSH(Arg(11)) with beta(+)-emitting radionuclides, to determine if the high sensitivity of positron emission tomography (PET) imaging would aid in the detection of malignant melanoma. DOTA-ReCCMSH(Arg(11)) was labeled with (64)Cu and (86)Y. Biodistribution and small animal PET imaging were carried out in mice implanted with B16/F1 murine melanoma tumor and compared with data obtained in the same animal model with [(18)F]FDG. In both cases a subset of animals were co-injected with 20 microg of DOTA-ReCCMSH(Arg(11)) to determine if tumor concentration was receptor mediated. Tumor concentration for both the (86)Y- and (64)Cu-complexes reached a maximum at 30 min, while coadministering 20 microg of unlabeled complex reduced tumor uptake significantly. Nontarget organ concentration was considerably lower with (86)Y-DOTA-ReCCMSH(Arg(11)) than its (64)Cu analogue, except in the kidneys, where the (64)Cu complex had lower accumulation at all time points. Small animal PET images for both complexes showed the tumor could be visualized after 30 min, with the standardized uptake value (SUV) analysis following a similar trend as the biodistribution data. The data obtained suggests that DOTA-ReCCMSH(Arg(11)), when labeled with beta(+)-emitting radionuclides, has the potential for early detection of malignant melanoma by exploiting the sensitivity and high resolution of PET.