In vitro and in vivo evaluation of novel ligands for radioimmunotherapy

Novel ligands cis-2,6-bis[N,N-bis(carboxymethyl)aminomethyl]-1-piperidineacetic acid (PIP-DTPA), cis-[(1R,11S)-6,9,15-Tris-carboxymethyl-3,6,9,15 -tetraazabicyclo[9.3.1]pentadec-3-yl] -acetic acid (PIP-DOTA), cis-{2,7-bis-[bis-earboxymethyl-amino)-methyl]-azepan-1-yl} -acetic acid (AZEP-DTPA), [2-(4,7 -bis-carboxymethyl-[1,4,7]triazacyclononan-1-yl-ethyl]-2-carbonylmethyl-amino]-tetraacetic acid (NETA) and {4-carboxymethyl-7-[2-(carboxymethylamino)-ethyl]-perhydro-1,4,7-triazonin-1-yl}-acetic acid (NPTA) are investigated as potential chelators of (LU)-L-177, Y-90, Pb-212 and Bi-213 for radioimmunotherapy (RIT). The new ligands are radiolabeled with Lu-177, Y-86/88/90 Pb-203 and Bi-205/6, and in vitro stability and in vivo stability of the radiolabeled complexes are assessed in human serum and athymic mice, respectively. In vitro studies indicate that all radiolabeled complexes with the exception of Y-90-AZEP-DTPA are stable in serum for 5-11 days. All new ligands examined herein are found to tightly hold Lu-177 in vivo. Piperidine-backboned DTPA (PIP-DTPA) complexes radiolabeled with all radioisotopes examined display excellent in vivo stability, that is, excretion without dissociation. The azepane-backboned DTPA derivative, AZEP-DTPA, appears ineffective in binding all but Lu-177 in vivo. NETA and NPTA radiolabeled with Y-86 or Lu-177 exhibit rapid blood clearance and low organ uptakes. Significant accretion in the kidney, femur and/or liver is observed with Pb-203-labeled AZEP-DTPA, PIP-DOTA and NPTA. Both Pb-203-PIP-DOTA and Bi-205/6-PIP-DOTA result in moderate to high renal accumulation of radioactivity. NETA exhibits improved renal accumulation with respect to PIP-DOTA for Bi-201/6 but also shows significant liver uptake. Of all ligands studied, only PIP-DTPA appears to effectively bind Pb-201 and Bi-205/6 in vivo. PIP-DTPA, PIP-DOTA, NETA and NPTA all show strong evidence of rapid blood clearance and low organ uptake for Lu-177 and Y-90. Serum stability and in vivo biodistribution results suggest PIP-DTPA as a potential chelating agent with broad applicability for use ill Lu-177, Y-90, Pb-212 and Bi-213 RIT. (c) 2006 Elsevier Inc. All rights reserved.