Biodistribution of 161Tb- or 177Lu-labeled immunoconjugate in comparison with its potential metallic radioactive degradation products and contaminants.

Radionuclides emitting beta- particles and Auger electrons present real or perspective radioactive components of radiopharmaceuticals used or developed for radionuclide therapy. Two important representatives of such radionuclides, lutetium-177 and terbium-161 have been applied as radiotoxic components of biomolecules and low-molecular agents developed for targeted radionuclide therapy. However, limited knowledge exists regarding the pharmacokinetics of potential contaminants or their final metabolic forms, such as chelate-radionuclide complexes or free radionuclides. These chemical forms can result from the radiolabeling process or the metabolism of radioimmunoconjugates in the organism. Since the pharmacokinetics of the undesired ionic forms of terbium-161 and lutetium-177 have not been fully explored using one experimental model and appropriate chemical forms of the radionuclides, this head-to-head study in mice was conducted. The experiment compared the biodistribution of a model 161Tb- or 177Lu-labeled antibody ramucirumab, 161Tb- or 177Lu-labeled DOTA-complexes, and free metal forms (161Tb3+ and 177Lu3+). Organ distribution was examined at selected time points (4 or 6, 24, 72, 144, and 240 h) following administration. Plasma binding was determined as an important distribution parameter. [161Tb]Tb-DOTA-ramucirumab and [177Lu]Lu-DOTA-ramucirumab distribution parameters exhibited typical pharmacokinetic characteristics of radioimmunoconjugates, such as a long elimination half-life and long-term retention in the liver or spleen. The general pharmacokinetic behavior of the congeners was very similar. A significant accumulation of free cationic form in bone and liver was observed. Whereas liver accumulation was transient, bone radioactivity did not decrease up to the last experimental interval. In contrast, [161Tb]Tb-DOTA and [177Lu]Lu-DOTA were eliminated rapidly from the organism without any significant organ retention. The high elimination rate of DOTA complexes was also supported by negligible binding to plasma. The obtained data demonstrate similar pharmacokinetic behavior for 161Tb- and 177Lu-labeled congeners, which may be useful for the development of future radiopharmaceuticals.