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

¹ Department of Dermatology, University of New Mexico, Albuquerque, New Mexico; College of Pharmacy, University of New Mexico, Albuquerque, New Mexico; Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico
² Department of Veterans Affairs Medical Center, Columbia, Missouri
³ Pacific Northwest National Laboratory, Richland, Washington
⁴ AlphaMed Inc., Acton, Massachusetts
⁵ Department of Veterans Affairs Medical Center, Columbia, Missouri; Department of Internal Medicine, University of Missouri, Columbia, Missouri; Department of Chemistry, University of Missouri, Columbia, Missouri
⁶ Department of Veterans Affairs Medical Center, Columbia, Missouri; Department of Biochemistry, University of Missouri, Columbia, Missouri; Department of Radiology, University of Missouri, Columbia, Missouri

^* To whom correspondence should be addressed. E-mail: ymiao{at}salud.unm.edu.

	Abstract

Peptide-targeted -therapy with 7.4 MBq of ²¹²Pb-[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]-ReO-[Cys^3,4,10,D-Phe⁷,Arg¹¹]-MSH_3–13 (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.

Key Words: molecular imaging, radiopharmaceuticals, peptides, ²⁰³Pb-labeled, melanoma imaging