Evaluation of ~(99m)Tc-Labeled Cyclic RGD Dimers: Impact of Cyclic RGD Peptides and ~(99m)Tc Chelates on Biological Properties

摘要

The main objective of this study is to explore the impact of cyclic RGD peptides and ~(99m)Tc chelates on biological properties of ~(99m)Tc radiotracers. Cyclic RGD peptide conjugates, HYNIC-K(NIC)-RGD2 (HYNIC = 6-hydrazinonicotinyl; RGD2 = E[c(RGDfK)]2 and NIC = nicotinyl), HYNIC-K(NIC)-3G-RGD2 (3G-RGD2 = Gly-Gly-Gly-E[Gly-Gly-Gly-c(RGDfK)]2), and HYNIC-K(NIC)-3P-RGD2 (3P-RGD2 = PEG4-E[PEG4-c(RGDfK)]2), were prepared. Macrocyclic ~(99m)Tc complexes [~(99m)Tc(HYNIC-K(NIC)-RGD2)-(tricine)] (l), [~(99m)Tc(HYNIC-K(NIC)-3G-RGD2)(tricine)] (2), and [~(99m)Tc-(HYNIC-K(NIC)-3P-RGD2)(tricine)] (3) were evaluated for their biodistribu-tion and tumor-targeting capability in athymic nude mice bearing MDA-MB-435 human breast tumor xenografts. It was found that 1, 2, and 3 could be prepared with high specific activity (～111 GBq/μmol). All three ~(99m)Tc radiotracers have two major isomers, which show almost identical uptake in tumors and normal organs. Replacing the bulky and highly charged [~(99m)Tc(HYNIC)(tricine)(TPPTS)] (TPPTS = trisodium triphenylphosphine-3,3',3"-trisulfonate) with a smaller [~(99m)Tc(HYNIC-K(NIC))(tricine)] resulted in less uptake in the kidneys and lungs for 3. Surprisingly, all three ~(99m)Tc radiotracers shared a similar tumor uptake (l, 5.73 ± 0.40%ID/g; 2, 5.24 ± 1.09%ID/g; and 3, 4.94 ± 1.71%ID/g) at 60 min p.i. The metabolic stability of ~(99m)Tc radiotracers depends on cyclic RGD peptides (3P-RGD2 > 3G-RGD2 ～ RGD2) and ~(99m)Tc chelates ([~(99m)Tc(HYNIC)(tricine)(TPPTS)] > [~(99m)Tc(HYNIC-K(NIC))(tricine)]). Immunohis-tochemical studies revealed a linear relationship between the α_vβ3 expression levels and tumor uptake or tumor/muscle ratios of 3, suggesting that 3 is useful for monitoring the tumor α_cβ3 expression. Complex 3 is a very attractive radiotracer for detection of integrin α_vβ3-positive tumors.