The Effect of A Hexanoic Acid Linker Insertion on the Pharmacokinetics and Tumor Targeting Properties of the Melanoma Imaging Agent 99mTc-HYNIC-cycMSH

Background: Lactam cyclized alpha-melanocyte stimulating hormone (α-MSH) analogues exhibit high stability and affinity for the MC1-R receptors over expressed in melanoma cells. Recently, we reported a novel ^99mTc-HYNIC-cycMSH_4-13 analogue with the HYNIC chelator directly attached to the lactam cyclized ring. Objective: In this study we proposed the introduction of a 6-aminohexanoic acid (Ahx) linker between the HYNIC chelator and lactam cyclized peptide cycMSH_4-13 to reduce steric hindrance and improve the melanoma targeting and imaging proprieties of the radiolabeled peptide. Method: HYNIC-Ahx-cycMSH_4-13 peptide was synthesized on an automated peptide synthesizer and displayed an IC⁵⁰ of 0.3 nM using B16/F1 cells. The ^99mTc/tricine radiolabeled peptide was examined for radiochemical purity, stability and cell binding. In vivo, biodistribution and planar gamma imaging studies were performed in B16/F1 melanoma tumor bearing C57BK mice. Results: ^99mTc-HYNIC-Ahx-cycMSH_4-13 was obtained with a radiochemical purity >95%, was stable up to 24 h at room temperature and exhibited high binding and rapid internalization in B16/F1 cells. In vivo biodistribution studies showed a tumor uptake of 4.92 ± 0.92 % ID/g and 2.78 ± 1.48 % ID/g at 2 h and 4 h post injection, respectively. Whole-body clearance was rapid through urinary excretion. The melanoma tumors were clearly visualized by planar gamma imaging. Conclusion: ^99mTc-HYNIC-Ahx-cycMSH_4-13was shown radiochemically stability and exhibited rapid and selective uptake in melanoma cells and tumors. Imaging studies yielded promising preclinical results, warranting further evaluation of ^99mTc-HYNIC-cycMSH analogs as melanoma specific imaging agents.

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