Pharmacokinetic modulation of radiolabeled chelates facilitated by phosphonate ester coordinating groups

Chelates are an important part of metal based radiopharmaceuticals. This study examines the possible application of phosphonate ester moieties incorporated into chelates, where the ester group can be changed to modulate the pharmacokinetics of the radiopharmaceutical, while the phosphonate stably binds the metal radioisotope. Two phosphonate ester containing chelates, PCTMB and PCTM(F)E, were compared to the carboxylate containing analogue, p-Bn-PCTA, with respect to radiochemistry with several radionuclides (In-111, Ga-68, Ga-67, Cu-64). The phosphonate ester derivatives were similar to p-Bn-PCTA with respect to efficient radiolabeling with each of the radiometals under mild, aqueous conditions. Each of the radiolabeled phosphonate esters was also shown to be stable under physiological conditions in vitro. The phosphonate ester moieties did exhibit a propensity to degrade under more acidic conditions. Biodistribution studies in mice with the In-111 radiolabeled versions of PCTMB, PCTM(F)E and p-Bn-PCTA demonstrated the ability of the phosphonate ester functionalities to change the pharmacokinetics of the BFCs. With increasing lipophilicity, the phosphonate ester derivatives showed increasing hepatic clearance; but no significant increase in background tissue uptake (bone, muscle) was observed, and all the In-111 radiolabeled BFCs were substantially cleared within 24 h. The substitution of phosphonate ester for carboxylate functional groups in chelates may be an effective strategy to assist in optimizing the pharmacokinetics of radiopharmaceuticals through varying of the ester group.