Biodistribution and Clearance of Small Molecule Hapten Chelates for Pretargeted Radioimmunotherapy

The favorable pharmacokinetics and clinical safety profile of metal-chelated 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) suggests that it might be an ideal hapten for pretargeted radioimmunotherapy. In an effort to minimize hapten retention in normal tissues and determine the effect of various chemical adducts on in vivo properties, a series of DOTA-based derivatives were evaluated. Biodistribution and whole-body clearance were evaluated for Lu-177-labeled DOTA, DOTA-biotin, a di-DOTA peptide, and DOTA-aminobenzene in normal CD1 mice. Kidney, liver, and bone marrow doses were estimated using standard Medical Internal Radiation Dose methodology. All haptens demonstrated similar low tissue and whole-body retention, with 2-4% of the injected dose remaining in mice 4 h postinjection. The kidney is predicted to be dose limiting for all Lu-177-labeled haptens tested with an estimated kidney dose of approximately 0.1 mGy/MBq. We present here a group of DOTA-based haptens that exhibit rapid clearance and exceptionally low whole-body retention 4 h postinjection. Aminobenzene, tyrosine-lysine, and biotin groups have minimal effects on the blood clearance and biodistribution of Lu-177-DOTA.