At the present time, no cure exists for metastatic melanoma due to its resistance to current chemotherapy and immunotherapy regimens. Hence, there is an urgency to develop novel imaging probes and more effective treatment approaches for melanoma detection and therapy. Melanocortin-1 (MC1) receptors have been used as targets for melanoma imaging and therapy due to their over-expression on human and mouse melanoma cells. Moreover, more than 80% of human metastatic melanoma tumor samples have been found to bear MC1 receptors. Radiolabeled alpha-melanocyte stimulating hormone (α-MSH) peptide analogues appear to be very promising candidates for melanoma imaging and therapy due to their nanomolar binding affinities to MC1 receptors. A novel class of metal-cyclized melanotropin peptide analogues (CCMSH) that target the MC1 receptors were developed to deliver diagnostic and therapeutic radionulides to melanoma cells for imaging and therapy. The MC1 receptor- targeting peptides (Arg11)CCMSH and DOTA-Re(Arg11)CCMSH were radiolabeled with 99mTc or 111In for melanoma imaging and 188Re or 212Pb to examine the melanoma therapeutic potential of targeted β and α particle radiation, respectively. Melanoma imaging was performed with 99mTc-(Arg11)CCMSH and 111In- DOTA-Re(Arg11)CCMSH in B16/F1 primary flank and B16/F10 pulmonary metastatic melanoma-bearing C57 mice. 99mTc-(Arg11)CCMSH and 111In-DOTA-Re(Arg11)CCMSH exhibited high receptor-mediated uptakes in primary flank melanoma (14.03±2.58 %ID/g at 1 h post-injection and 17.29±2.49 %ID/g at 2 h post-injection) and significant higher (p<0.05) uptakes in metastatic melanoma-bearing lung compared to normal lung. Both primary flank melanoma and pulmonary metastatic melanoma tumors were clearly imaged by micro-SPECT/CT images of 99mTc-(Arg11)CCMSH and 111In-DOTA-Re(Arg11)CCMSH. The therapeutic efficacy of 188Re labeled (Arg11)CCMSH and 212Pb labeled DOTA-Re(Arg11)CCMSH was examined in B16/F1 flank melanoma-bearing C57 mice. Mice were administered 200, 2x400 and 600 µCi of 188Re-(Arg11)CCMSH or 50, 100 and 200 µCi of 212Pb-[DOTA]-Re(Arg11)CCMSH via the tail vein. Non-treated mice received a saline placebo. The tumor growth rate was reduced and the survival rate was prolonged in the treatment groups. Treatment with 2×400 μCi of 188Re-(Arg11)CCMSH significantly extended the mean life of B16/F1 tumor mice from 9.4 to 13.3 days (p<0.05). In comparison with 188Re-(Arg11)CCMSH, 212Pb-[DOTA]-Re(Arg11)CCMSH exhibited superior therapeutic effects. Treatment with 50 µCi and 100 µCi doses of 212Pb-[DOTA]-Re(Arg11)CCMSH prolonged the mean life of B16/F1 tumor mice from 14.6 to 22.0 days (p=0.004) and 28.0 days (p=0.002), respectively. The 200 µCi treatment group exhibited the best survival statistics (45.0 days mean survival, p=0.01). Forty-four percent of the mice receiving a 200 µCi dose and 20% of the mice from the 100 µCi treatment group were free of tumor and survived the entire 120-day study. Excellent tumor targeting properties of 99mTc, 188Re labeled (Arg11)CCMSH and 111In, 212Pb labeled DOTA-Re(Arg11)CCMSH peptide analogues highlight their potential as novel radiopharmaceuticals for melanoma detection and therapy.

[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]