203Pb-Labeled α-Melanocyte–Stimulating Hormone Peptide as an Imaging Probe for Melanoma Detection

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Abstract
Peptide-targeted α-therapy with 7.4 MBq of 212Pb-[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-ReO-[Cys3,4,10,d-Phe7,Arg11]α-MSH3–13 (212Pb-DOTA-Re(Arg11)CCMSH) cured 45% of B16/F1 murine melanoma–bearing C57 mice in a 120-d study, highlighting its melanoma treatment potential. However, there is a need to develop an imaging surrogate for patient-specific dosimetry and to monitor the tumor response to 212Pb-DOTA-Re(Arg11)CCMSH therapy. The purpose of this study was to evaluate the potential of 203Pb-DOTA-Re(Arg11)CCMSH as a matched-pair SPECT agent for 212Pb-DOTA-Re(Arg11)CCMSH. Methods: DOTA-Re(Arg11)CCMSH was labeled with 203Pb in 0.5 M NH4OAc buffer at pH 5.4. The internalization and efflux of 203Pb-DOTA-Re(Arg11)CCMSH were determined in B16/F1 melanoma cells. The pharmacokinetics of 203Pb-DOTA-Re(Arg11)CCMSH was examined in B16/F1 melanoma–bearing C57 mice. A micro-SPECT/CT study was performed with 203Pb-DOTA-Re(Arg11)CCMSH in a B16/F1 melanoma–bearing C57 mouse at 2 h after injection. Results: 203Pb-DOTA-Re(Arg11)CCMSH was easily prepared in NH4OAc buffer and completely separated from the excess nonradiolabeled peptide by reversed-phase high-performance liquid chromatography (RP-HPLC). 203Pb-DOTA-Re(Arg11)CCMSH displayed fast internalization and extended retention in B16/F1 cells. Approximately 73% of 203Pb-DOTA-Re(Arg11)CCMSH activity internalized after a 20-min incubation at 25°C. After incubation of the cells in culture medium for 20 min, 78% of internalized activity remained in the cells. 203Pb-DOTA-Re(Arg11)CCMSH exhibited a biodistribution pattern similar to that of 212Pb-DOTA-Re(Arg11)CCMSH in B16/F1 melanoma–bearing mice. 203Pb-DOTA-Re(Arg11)CCMSH exhibited a peak tumor uptake of 12.00 ± 3.20 percentage injected dose per gram (%ID/g) at 1 h after injection. The tumor uptake gradually decreased to 3.43 ± 1.12 %ID/g at 48 h after injection. 203Pb-DOTA-Re(Arg11)CCMSH exhibited a peak tumor-to-kidney uptake ratio of 1.53 at 2 h after injection. The absorbed doses to the tumor and kidneys were 4.32 and 4.35 Gy, respectively, per 37 MBq. Whole-body clearance of 203Pb-DOTA-Re(Arg11)CCMSH was fast, with approximately 89% of the injected activity cleared through the urinary system by 2 h after injection. 203Pb showed 1.6-mm SPECT resolution, which was comparable to 99mTc. Melanoma lesions were visualized through SPECT/CT images of 203Pb-DOTA-Re(Arg11)CCMSH at 2 h after injection. Conclusion: 203Pb-DOTA-Re(Arg11)CCMSH exhibited favorable pharmacokinetic and tumor imaging properties, highlighting its potential as a matched-pair SPECT agent for 212Pb-DOTA-Re(Arg11)CCMSH melanoma treatment.

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