In vivo evaluation of ¹⁸⁸re-labeled alpha-melanocyte stimulating hormone peptide analogs for melanoma therapy

The purpose of our study was to optimize melanoma tumor uptake of ¹⁸⁸Re-CCMSH and reduce its nonspecific kidney retention. Nephrotoxicity is often a serious problem associated with targeted radiotherapy, therefore, increasing the tumor/kidney uptake ratio of ¹⁸⁸Re-CCMSH is crucial for optimizing its therapeutic efficacy. Structural modification of the peptide and amino acid co-infusion were investigated as strategies to improve the tumor/kidney uptake ratio of ¹⁸⁸Re-CCMSH. The substitution of Lys¹¹ with Arg¹¹ was examined to determine if removal of lysine from the peptide would improve kidney clearance without sacrificing tumor uptake. The pharmacokinetics of ¹⁸⁸Re-CCMSH and ¹⁸⁸Re(Arg¹¹)CCMSH were determined in B16/F1 murine melanomabearing C57 mice. Tumor uptake values of ¹⁸⁸Re-CCMSH and ¹⁸⁸Re-(Arg¹¹)CCMSH were 15.03 ± 5.20% ID/g and 20.44 ± 1.91% ID/g at 1 hr postinjection and 1.94 ± 0.47% ID/g and 3.50 ± 2.32% ID/g at 24 hr postinjection. Renal retention of ¹⁸⁸Re-(Arg¹¹)CCMSH was 11.79 ± 1.29 ID/g and 3.67 ± 0.51 ID/g at 1 hr and 4 hr postinjection, which was a greater than 50% reduction compared to ¹⁸⁸Re-CCMSH. The Arg for Lys substitution in ¹⁸⁸Re-(Arg¹¹)CCMSH resulted in improved tumor uptake and reduced kidney retention. Renal retention of both ¹⁸⁸Re-CCMSH and ¹⁸⁸Re-(Arg¹¹)CCMSH were significantly reduced by co-injection of 20 mg of L-lysine, Larginine and a combination of L-lysine:L-arginine. Tumor/ kidney uptake values for ¹⁸⁸Re-CCMSH and ¹⁸⁸Re-(Arg¹¹)CCMSH were maximally reduced by 52.9% and 46.3%, respectively. However, even with amino acid co-injection, the tumor/kidney ratio of ¹⁸⁸Re-CCMSH was lower than that of ¹⁸⁸Re-(Arg¹¹)CCMSH. Improved tumor uptake and reduced kidney retention of ¹⁸⁸Re-(Arg¹¹)CCMSH will facilitate targeted irradiation of melanoma tumors while minimizing the dose to the kidneys.