Comparative evaluation of99mTc-MAG2-oligodeoxynucleotides with phosphodiester or phosphorothioate backbones: preparation, stability and biodistribution

Abstract

Antisense oligodeoxynucleotides (ODNs) conjugated to a suitable bifunctional chelating agent and labelled with a suitable radionuclide could become useful in the diagnosis and differentiation of cancers. Radiolabelled natural DNA with phosphodiester (PO) backbone is a candidate for use in imaging, while phosphorothioate (PS) ODNs already are proving their efficacy in antisense therapy. In this study, two PO and two PS ODNs have been conjugated with the N2SO chelator MAG2 in a procedure designed to make a N3S tetraligand which forms stable complexes with technetium-99m. Depending on the S-protecting group used and reaction conditions employed, labelling yields of more than 90% can routinely be obtained. The 99mTc-MAG2-ODNs are stable in solution, even in the presence of a 30-fold excess of cysteine. However, at higher concentrations of cysteine and in foetal calf serum they are not stable. In vivo in mice, the PO 99mTc-MAG2-ODNs are degraded more than 50% in 5 min, while the PS analogues remain intact. The PS and PO 99mTc-MAG2-ODNs are distributed in a similar fashion in normal mice, except for a higher liver retention of the PO 99mTc-MAG2-ODNs at 60 min. Copyright © 1999 John Wiley & Sons, Ltd.