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

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 (L1) or 1,7-positions (L2) of the cyclen ring. In radiolabeling reactions of L1 or L2 with the γ-emitting radioisotope, [111In]In3+, we have observed radiometal-mediated hydrolysis of a single
amide group of either L1 or L2. The reaction of either [111In]In3+ or [natIn]In3+ with either L1 or L2, in aqueous alkaline solutions at 80 °C, initially results
in formation of [In(L1)]+ or [In(L2)]+, respectively. Over time, each of these species undergoes In3+-mediated hydrolysis of a single amide group to yield species
in which In3+ 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 L1 complex
compared to that for the L2 complex.
Density functional theory calculations corroborate these experimental
findings and importantly indicate that the activation energy required
for the hydrolysis of L1 is significantly
lower than that required for L2. 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.