Radiosynthesis of New [90Y]-DOTA-Based Maleimide Reagents Suitable for the Prelabeling of Thiol-Bearing L-Oligonucleotides and Peptides

We describe the radiosynthesis of two new [Y-90]-DOTA-based maleimide reagents, suitable for the mild radiolabeling of L-RNAs and peptides modified with thiol-bearing linkers. The synthesis procedure of both maleimide-bearing Y-90 complexes, [{(2S)-2-[4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl}tetraacelato][Y-90]yttrate(1-)([(OY)-O-90]3) and [{(2S)-2-(4-{[4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoyl]amino}benzyl)1,4,7,10-tetraaza-cyclododecane-1,4,7,10-tetrayl]tetraacetato} [Y-90]yttrate(1-)([Y-90]4), was optimized in terms of an easy purification method via solid-phase extraction (SPE). Application as well as reactivity of both maleimide reagents were initially evaluated by the prelabeling of glutathione (GSH) and a thiol-modified 12mer L-RNA as model substances. In comparison to the N-aryl maleimide-bearing complex [Y-90]3, N-alkyl maleimide-bearing complex [Y-90]4 showed an increased hydrolytic stability at pH >= 7. A slightly higher reactivity was found for [Y-90]3 by prelabeling of 0.1 and I jig glutathione, respectively, in phosphate buffer (pH 7.2) at room temperature. In terms of very high radiochemical yields, the direct radiolabeling of DOTA-L-RNA conjugate with [Y-90]YCl3 proved to be more suitable than the prelabeling of the thiol-modified 12mer L-RNA derivative with [Y-90]4.