Radiolabeling of HTE1PA: A new monopicolinate cyclam derivative for Cu-64 phenotypic imaging. In vitro and in vivo stability studies in mice

Nucl Med Biol. 2014 May:41 Suppl:e49-57. doi: 10.1016/j.nucmedbio.2013.12.009. Epub 2013 Dec 18.

Abstract

Introduction: HTE1PA, a monopicolinate-N-alkylated cyclam-based ligand has previously demonstrated fast complexation process, high kinetic inertness and important thermodynamic and electrochemical stability with respect to natural copper. In this work we first developed a new synthetic route to obtain HTE1PA in good yields. Then, we investigated HTE1PA chelation properties towards copper-64 and assessed in vitro and in vivo stability of the resulting compound.

Methods: Radiolabeling of HTE1PA with copper-64 was tested at different ligand concentrations in ammonium acetate medium. In vitro stability study was carried out by incubating [(64)Cu]TE1PA complex in human serum at both 37°C and 4°C; chromatographic controls were performed over 24h. Biodistribution, pharmacokinetic and hepatic metabolism of [(64)Cu]TE1PA were conducted in BALC/c mice in comparison with [(64)Cu]acetate and [(64)Cu]DOTA, used as a reference ligand.

Results: The promising results obtained for natural copper complexation were confirmed. HTE1PA was quantitatively radiolabeled in 15 min at room temperature. The resulting complex showed high serum stability. [(64)Cu]TE1PA induced a significant uptake in the liver and kidneys at early biodistribution time point. Nevertheless, a high speed wash out was observed at 24h leading to significantly lower uptake into the liver compared to [(64)Cu]DOTA. The metabolism study was consistent with a high resistance to transchelation as the initial uptake into liver matches with the intact form of [(64)Cu]TE1PA.

Conclusion: Despite the partial elimination of HTE1PA - as copper-64 complex - through the hepatic route, its high selectivity for copper and its resistance to transchelation make it a promising ligand for antibody radiolabeling with either copper-64 or copper-67.

Keywords: Chelating agents; Copper radioisotopes; Cyclam; DOTA; Metabolism; Radiopharmaceuticals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Copper Radioisotopes*
  • Drug Stability
  • Female
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / metabolism
  • Heterocyclic Compounds / pharmacokinetics
  • Heterocyclic Compounds, 1-Ring / chemistry*
  • Heterocyclic Compounds, 1-Ring / metabolism
  • Heterocyclic Compounds, 1-Ring / pharmacokinetics
  • Humans
  • Isotope Labeling / methods*
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Molecular Imaging / methods*
  • Phenotype*
  • Picolinic Acids / chemistry*
  • Picolinic Acids / metabolism
  • Picolinic Acids / pharmacokinetics
  • Tissue Distribution

Substances

  • Copper Radioisotopes
  • HTE1PA compound
  • Heterocyclic Compounds
  • Heterocyclic Compounds, 1-Ring
  • Picolinic Acids
  • 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
  • cyclam