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 (Cl) 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 (H(4)d3a-py(NO-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-[In-111(do3a-py(NO-C))] and G4-[In-111(do3a-py(NO-C))]. were kinetically stable for at least 48 h 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-[In-111(do3a-py(NO-C))] conjugate than G4-[In-111(do3a-PyNO-C)] conjugate. However, the G1-[In-111(do3a-py(NO-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[In-111(do3a-py(NO-C))] conjugate. (C) 2011 Elsevier B.V. All rights reserved.