Radiochemistry, biodistribution and imaging study of 161Tb and 155Tb labeled crown-αMSH for MC1R targeting theranostics

Introduction: Worldwide, the incidents of melanoma have steadily increased over the last 50 years. In the US, the annual newly diagnosed cases of invasive melanoma increased by 44% in the past decade. Despite recent advances in treatments, the prognosis for late-stage melanoma remains particularly poor, with an average five-year survival rate of 22.5% for instances of metastatic disease. Since traditional chemotherapy for metastatic melanomas shows poor efficacy, targeted radionuclide therapy (TRT) with emerging powerful radionuclides offers an interesting alternative for treating advanced disease.

The melanocortin 1 receptor (MC1R) is specifically expressed in most melanomas, while normal healthy tissues show no significant expression, making it an interesting target for TRT development. Synthetic α-melanocyte-stimulating hormone (αMSH) analogues are peptides with high affinities for MC1R, and have been labeled with ¹⁸F, ⁶⁸Ga, ¹⁷⁷Lu, ²¹²Pb, and ²²⁵Ac and have demonstrated efficacy for imaging or therapy.

Terbium (Tb) is one of the few elements which possesses isotopes suitable for both imaging and therapy, enabling theranostics with chemically identical radiopharmaceuticals. ¹⁶¹Tb (t_1/2 6.89 d) is a promising therapeutic isotope that emits beta-particles along with Auger and conversion electrons. ¹⁵⁵Tb (t_1/2 5.32 d) is a SPECT imaging isotope with Auger and conversion electrons. In this report, we demonstrate for the first time the radiochemistry and initial preclinical studies of ¹⁶¹Tb and ¹⁵⁵Tb labeled crown-αMSH, a MC1R targeting peptide conjugated with a non-conventional chelator.

Methods: Crown-αMSH, a chelator conjugated peptide targeting MC1R, was synthesized. The labeling conditions with ¹⁵⁵Tb were investigated. Stabilities of the labelled peptide in buffer and human serum were studied. The in vivo uptake in mice bearing B16F10 tumors was examined for both ¹⁶¹Tb-crown-αMSH and ¹⁵⁵Tb-crown-αMSH. SPECT imaging for ¹⁵⁵Tb-crown-aMSH was recorded.

Results: Crown-αMSH can be labeled efficiently with both ¹⁶¹Tb and ¹⁵⁵Tb (≥88% at 10^-5 M) at ambient temperature under mild conditions. ¹⁵⁵Tb-crown-αMSH exhibits impressive stability in solution, maintaining > 97% radiochemical integrity when challenged in human serum or aqueous buffer over 7 days. ¹⁶¹Tb and ¹⁵⁵Tb-crown-αMSH showed very similar biodistribution profiles at 2 hours post injection in B16F10 tumor bearing mice. For both radiopharmaceuticals, we observed effective tumor accumulation, good image contrast and low uptake in other tissues and organs (Figure 1).

Conclusions: ¹⁶¹Tb/¹⁵⁵Tb labeled crown-αMSH is a promising TRT agent for melanoma imaging and therapy and warrants further preclinical investigations.

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