Theranostic Radiotracers for Melanoma Imaging and Therapy: A Comparative Study of Subcutaneous and Intradermal Tumor Models Using DOTA-Re-CCMSH Peptides

<b><i>Introduction:</i></b> Melanoma, with its aggressive behavior and high metastatic potential, presents significant clinical challenges. The melanocortin-1 receptor (MC1R) is a promising target for diagnosis and therapy due to its overexpression in metastatic melanoma. <b><i>Methods:</i></b> This study compares the theranostic potential of DOTARe-CCMSH, labeled with ⁶⁸Ga and ¹⁷⁷Lu, in subcutaneous and intradermal murine melanoma models over an extended period. Radiolabeling achieved high molar activities for both isotopes, enabling precise imaging and therapeutic applications. <b><i>Results:</i></b> PET imaging with [⁶⁸Ga]Ga-DOTA-Re-CCMSH showed specific tumor accumulation, with a mean uptake of 2.25 ± 0.2% ID/g at 2 hours post-injection, enhanced by gelofusine pre-administration. SPECT imaging with [¹⁷⁷Lu]LuDOTA-Re-CCMSH revealed significant and sustained tumor uptake in both models, with mean values of 21.9 ± 7.98 for subcutaneous and 19.8 ± 5.36 for intradermal tumors at 4 hours post-injection, extending up to 24 hours. This study tracked the therapeutic radiotracer uptake for up to 7 days post-injection, showing continued retention and tumor specificity, especially in the tumor-to muscle ratio, which reached 172 at 24 hours. <b><i>Discussion and Conclusions:</i></b> Comparative biodistribution analyses highlighted differences between subcutaneous and intradermal models, including distinct peritumoral edema arrangements. These findings emphasize the value of long-term theranostic studies in understanding tumor behavior and the efficacy of radiolabeled peptides in melanoma treatment, advancing personalized oncology approaches.