2-Mercaptoacetylglycylglycyl (MAG2) as a bifunctional chelator for 99mTc-labeling of cyclic RGD dimers: effect of technetium chelate on tumor uptake and pharmacokinetics.

This report describes the synthesis of MAG(2)-PEG(4)-E[c(RGDfK)](2) (MAG(2)-P-RGD(2): MAG(2) = S-benzoylmercaptoacetylglycylglycyl; PEG(4) = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and MAG(2)-PEG(4)-E[PEG(4)-c(RGDfK)](2) (MAG(2)-3P-RGD(2)), and the evaluation of (99m)TcO(MAG(2)-P-RGD(2)) and (99m)TcO(MAG(2)-3P-RGD(2)) as new radiotracers for tumor imaging in the athymic nude mice bearing U87MG human glioma xenografts. We found that MAG(2) is such an efficient bifunctional chelating agent that (99m)TcO(MAG(2)-P-RGD(2)) and (99m)TcO(MAG(2)-3P-RGD(2)) coul d be prepared in high yield (>90%) with high specific activity (∼5 Ci/μmol) using a kit formulation. (99m)TcO(MAG(2)-P-RGD(2)) and (99m)TcO(MAG(2)-3P-RGD(2)) have very high solution stability in the kit matrix. Biodistribution data in athymic nude mice bearing U87MG human glioma xenografts indicated that replacing the highly charged [(99m)Tc(HYNIC = 6-hydrazinonicotinyl and TPPTS = trisodium triphenylphosphine-3,3',3''-trisulfonate) with smaller (99m)TcO(MAG(2)) resulted in a significant increase in the radiotracer uptake in the tumor and normal organs most likely due to the higher lipophilicity of (99m)TcO(MAG(2)-3P-RGD(2)) (log P = -3.15 ± 0.10) than that for [(99m)Tc(HYNIC-3P-RGD(2))(tricine)(TPPTS)] ((99m)Tc-3P-RGD(2): log P = -3.96 ± 0.05). Even though (99m)TcO(MAG(2)-3P-RGD(2)) has better tumor uptake (15.36 ± 2.17 %ID/g at 60 min postinjection (p.i.)) than (99m)Tc-3P-RGD(2) (9.15 ± 2.13 %ID/g at 60 min p.i.), its tumor-to-background (T/B) ratios (tumor/blood = 13.52 ± 4.57; tumor/liver = 4.25 ± 0.88; tumor/lung = 3.17 ± 0.60; and tumor/muscle = 8.34 ± 2.34) are not as good as those of (99m)Tc-3P-RGD(2) (tumor/blood = 36.0 ± 11.5; tumor/liver = 5.14 ± 1.46; tumor/lung = 4.36 ± 0.54; and tumor/muscle = 13.70 ± 2.21) at 60 min p.i. On the basis of these results, we believe that (99m)Tc-3P-RGD(2) remains a better radiotracer because of its higher T/B ratios.