Development of an in vitro model for assessing the in vivo stability of lanthanide chelates

An in vitro model was developed to evaluate the in vivo stability of lantha nide polyaminocarboxylate complexes. The ligand-to-metal ratios for the che lates EDTA, CDTA, DTPA, MA-DTPA (monoamide-DTPA) and DOTA with the lanthani des lanthanum, samarium, and lutetium were optimized to achieve greater tha n or equal to 98% complexation yield for the resultant radiolanthanide comp lexes. The exchange of the radiolanthanides from their EDTA, CDTA, DTPA, MA -DTPA and DOTA complexes with Ca2+ was determined by in vitro adsorption an d in vitro column studies using hydroxyapatite (HA), an in vitro bone model . In vitro serum stability of these radiolanthanide complexes was used as a n additional indicator of in vivo stability, although the mechanism of inst ability in serum will be different than with bone. The in vitro studies wer e consistent with the expected findings that the smallest lanthanide (Lu) f ormed the most stable complexes. In vivo studies were done to validate the in vitro model. Biodistribution studies in normal CF-1 mice showed that in vivo stability of the complex (i.e., the more lanthanide remaining in compl ex form) could be assessed by a combination of the urinary, bone and liver uptake. For example, biodistribution studies demonstrate that high urinary excretion correlated with complex stability, while high liver plus bone upt ake correlated with complex instability. The urinary excretion of the EDTA complexes decreased from Lu-177 to La-140 indicating a loss in stability in the direction of La-140, consistent with the in vitro studies. The more st able a lanthanide complex is, the lower its exchange with HA in vitro will be, and the lower its combined bone plus liver uptake and higher its urinar y excretion will be in vivo. This investigation indicates that the in vivo stability can be determined by a screening method that measures the degree of exchange from the lanthanide chelate with hydroxyapatite (HA) and its se rum stability. (C) 2001 Elsevier Science Inc. All rights reserved.