Probing Unexpected Reactivity in Radiometal Chemistry: Indium-111-Mediated Hydrolysis of Hybrid Cyclen-Hydroxypyridinone Ligands

[Image: see text] Chelators based on hydroxypyridinones have utility in incorporating radioactive metal ions into diagnostic and therapeutic agents used in nuclear medicine. Over the course of our hydroxypyridinone studies, we have prepared two novel chelators, consisting of a cyclen (1,4,7,10-tetraazacyclododecane) ring bearing two pendant hydroxypyridinone groups, appended via methylene acetamide motifs at either the 1,4-positions (L(1)) or 1,7-positions (L(2)) of the cyclen ring. In radiolabeling reactions of L(1) or L(2) with the γ-emitting radioisotope, [(111)In]In(3+), we have observed radiometal-mediated hydrolysis of a single amide group of either L(1) or L(2). The reaction of either [(111)In]In(3+) or [(nat)In]In(3+) with either L(1) or L(2), in aqueous alkaline solutions at 80 °C, initially results in formation of [In(L(1))](+) or [In(L(2))](+), respectively. Over time, each of these species undergoes In(3+)-mediated hydrolysis of a single amide group to yield species in which In(3+) remains coordinated to the resultant chelator, which consists of a cyclen ring bearing a single hydroxypyridinone group and a single carboxylate group. The reactivity toward hydrolysis is higher for the L(1) complex compared to that for the L(2) complex. Density functional theory calculations corroborate these experimental findings and importantly indicate that the activation energy required for the hydrolysis of L(1) is significantly lower than that required for L(2). This is the first reported example of a chelator undergoing radiometal-mediated hydrolysis to form a radiometalated complex. It is possible that metal-mediated amide bond cleavage is a source of instability in other radiotracers, particularly those in which radiometal complexation occurs in aqueous, basic solutions at high temperatures. This study highlights the importance of appropriate characterization of radiolabeled products.