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 [⁹⁰Y]-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 ⁹⁰Y 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}tetraacetato][⁹⁰Y]yttrate(1-)([⁹⁰Y]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}[⁹⁰Y]yttrate(1-)([⁹⁰Y]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 [⁹⁰Y]3, N-alkyl maleimide-bearing complex [⁹⁰Y]4 showed an increased hydrolytic stability at pH ≥ 7. A slightly higher reactivity was found for [⁹⁰Y]3 by prelabeling of 0.1 and 1 μg 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 [⁹⁰Y]YCl₃ proved to be more suitable than the prelabeling of the thiol-modified 12mer l-RNA derivative with [⁹⁰Y]4.