title: In vitro and in vivo evaluation of novel ligands for radioimmunotherapy.
abstract: 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-carboxymethyl-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 177Lu, 90Y, 212Pb and 213Bi for radioimmunotherapy (RIT). The new ligands are radiolabeled with 177Lu, 86/88/90Y, 203Pb and 205/6Bi, 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 90Y-AZEP-DTPA are stable in serum for 5-11 days. All new ligands examined herein are found to tightly hold 177Lu 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 177Lu in vivo. NETA and NPTA radiolabeled with 86Y or 177Lu exhibit rapid blood clearance and low organ uptakes. Significant accretion in the kidney, femur and/or liver is observed with 203Pb-labeled AZEP-DTPA, PIP-DOTA and NPTA. Both 203Pb-PIP-DOTA and 205/6Bi-PIP-DOTA result in moderate to high renal accumulation of radioactivity. NETA exhibits improved renal accumulation with respect to PIP-DOTA for 205/6Bi but also shows significant liver uptake. Of all ligands studied, only PIP-DTPA appears to effectively bind 203Pb and 205/6Bi in vivo. PIP-DTPA, PIP-DOTA, NETA and NPTA all show strong evidence of rapid blood clearance and low organ uptake for 177Lu and 90Y. Serum stability and in vivo biodistribution results suggest PIP-DTPA as a potential chelating agent with broad applicability for use in 177Lu, 90Y, 212Pb and 213Bi RIT.
authors.affiliation: Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA. chong@iit.edu
authors.forename: Hyun-Soon
authors.initials: HS
authors.lastname: Chong
authors.forename: Diane E
authors.initials: DE
authors.lastname: Milenic
authors.forename: Kayhan
authors.initials: K
authors.lastname: Garmestani
authors.forename: Erik D
authors.initials: ED
authors.lastname: Brady
authors.forename: Hans
authors.initials: H
authors.lastname: Arora
authors.forename: Candice
authors.initials: C
authors.lastname: Pfiester
authors.forename: Martin W
authors.initials: MW
authors.lastname: Brechbiel
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002614:Chelating Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D015195:Drug Design; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D007553:Isotope Labeling / Q000379:methods; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009928:Organ Specificity; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016499:Radioimmunotherapy / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: C512979:(2,7-bis(bis(carboxymethylamino)methyl)azepan-1-yl)acetic acid; C512978:(6,9,15-triscarboxymethyl-3,6,9,15-tetraazabicyclo(9.3.1)pentadec-3-yl)acetic acid; C512977:2,6-bis(N,N-bis(carboxymethyl)aminomethyl)-1-piperidineacetic acid; D000085:Acetates; D001381:Azepines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002614:Chelating Agents; D010880:Piperidines; D019275:Radiopharmaceuticals; D005998:Glycine