99mTc-Galacto-RGD2: A novel 99mTc-labeled cyclic RGD peptide dimer useful for tumor imaging

摘要

This study sought to evaluate [99mTc(HYNIC-Galacto-RGD 2)(tricine)(TPPTS)] (99mTc-Galacto-RGD2: HYNIC = 6-hydrazinonicotinyl; Galacto-RGD2 = Glu[cyclo[Arg-Gly-Asp-d-Phe- Lys(SAA-PEG2-(1,2,3-triazole)-1-yl-4-methylamide)]]2 (SAA = 7-amino-l-glycero-l-galacto-2,6-anhydro-7-deoxyheptanamide, and PEG 2 = 3,6-dioxaoctanoic acid); and TPPTS = trisodium triphenylphosphine-3,3′,3″-trisulfonate) as a new radiotracer for tumor imaging. Galacto-RGD2 was prepared via the copper(I)-catalyzed 1,3-dipolar azide-alkyne Huisgen cycloaddition. HYNIC-Galacto-RGD2 was prepared by reacting Galacto-RGD2 with sodium succinimidyl 6-(2-(2-sulfonatobenzaldehyde)hydrazono)nicotinate (HYNIC-OSu) in the presence of diisopropylethylamine, and was evaluated for its integrin αvβ3 binding affinity against 125I-echistatin bound to U87MG glioma cells. The IC50 value for HYNIC-Galacto-RGD2 was determined to be 20 ± 2 nM. 99mTc-Galacto-RGD2 was prepared in high specific activity (～185 GBq/μmol) and high radiochemical purity (95%), and was evaluated in athymic nude mice bearing U87MG glioma xenografts for its tumor-targeting capability and biodistribution. The tumor uptake of 99mTc-Galacto-RGD2 was 10.30 ± 1.67, 8.37 ± 2.13, 6.86 ± 1.33, and 5.61 ± 1.52%ID/g at 5, 30, 60, and 120 min p.i., respectively, which was in agreement with high integrin αvβ3 expression on glioma cells and neovasculature. Its lower uptake in intestines, lungs, and spleen suggests that 99mTc-Galacto-RGD2 has advantages over 99mTc-3P-RGD2 ([99mTc(HYNIC-3P-RGD 2)(tricine)(TPPTS)]: 3P-RGD2 = PEG4-E[PEG 4-c(RGDfK)]2; PEG4 = 15-amino-4,7,10,13- tetraoxapentadecanoic acid) for imaging tumors in the chest and abdominal regions. U87MG tumors were readily detected by SPECT and the tumor uptake of 99mTc-Galacto-RGD2 was integrin αvβ 3-specific. 99mTc-Galacto-RGD2 also had very high metabolic stability. On the basis of results from this study, it was concluded that 99mTc-Galacto-RGD2 is an excellent radiotracer for imaging integrin αvβ3-positive tumors and related metastases.