Radiolabeling of PAMAM dendrimers conjugated to a pyridine-N-oxide DOTA analog with 111In: Optimization of reaction conditions and biodistribution

Polyamidoamine dendrimers (PAMAMs) of generations 1 (G1) and 4 (G4) were conjugated with a bifunctional pyridine-N-oxide DOTA analog, 10-[(4-carboxy-1-oxidopyridin-2-yl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (H4do3a-pyNO−C), through the pyridine-4-carboxylic acid group, and the conjugates were radiolabeled with indium-111. Reaction conditions for the radiolabelling were optimized. Both radiolabeled conjugates, G1-[111In(do3a-pyNO−C)] and G4-[111In(do3a-pyNO−C)], were kinetically stable for at least 48h after preparation; in the presence of competitive ligands, the radiochemical purity of the conjugates slightly decreased (4–7%) over the same time period. The preclinical pharmacokinetics of both agents were evaluated. Biodistribution and elimination in rats were more favorable for the G1-[111In(do3a-pyNO−C)] conjugate than G4-[111In(do3a-pyNO−C)] conjugate. However, the G1-[111In(do3a-pyNO−C)] conjugate was rapidly eliminated from the body, mainly through urine, while, significant and long-term radioactivity uptake in the liver and kidney was observed for the G4-[111In(do3a-pyNO−C)] conjugate.