A semi rigid novel hydroxamate AMPED-based ligand for89 Zr PET imaging

Lisa Russelli, Francesco De Rose, Loredana Leone, Sybille Reder, Markus Schwaiger, Calogero D’Alessandria, Lorenzo Tei

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

In this work, we designed, developed, characterized, and investigated a new chelator and its bifunctional derivative for89 Zr labeling and PET-imaging. In a preliminary study, we synthesized two hexadentate chelators named AAZTHAS and AAZTHAG, based on the seven-membered hetero-cycle AMPED (6-amino-6-methylperhydro-1,4-diazepine) with the aim to increase the rigidity of the89 Zr complex by using N-methyl-N-(hydroxy)succinamide or N-methyl-N-(hydroxy)glutaramide pendant arms attached to the cyclic structure. N-methylhydroxamate groups are the donor groups chosen to efficiently coordinate89 Zr. After in vitro stability tests, we selected the chelator with longer arms, AAZTHAG, as the best complexing agent for89 Zr presenting a stability of 86.4 ± 5.5% in human serum (HS) for at least 72 h. Small animal PET/CT static scans acquired at different time points (up to 24 h) and ex vivo organ distribution studies were then carried out in healthy nude mice (n = 3) to investigate the stability and biodistribution in vivo of this new89 Zr-based complex. High stability in vivo, with low accumulation of free89 Zr in bones and kidneys, was measured. Furthermore, an activated ester functionalized version of AAZTHAG was synthesized to allow the conjugation with biomolecules such as antibodies. The bifunctional chelator was then conjugated to the human anti-HER2 monoclonal antibody Trastuzumab (Tz) as a proof of principle test of conjugation to biologically active molecules. The final89 Zr labeled compound was characterized via radio-HPLC and SDS-PAGE followed by autoradiography, and its stability in different solutions was assessed for at least 4 days.

Original languageEnglish
Article number5819
JournalMolecules
Volume26
Issue number19
DOIs
StatePublished - 1 Oct 2021
Externally publishedYes

Keywords

  • Hydroxamates
  • Labeling
  • PET-imaging
  • Polydentate chelators
  • Zirconium-89

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