Bifunctional chelators for copper radiopharmaceuticals: the synthesis of [Cu(ATSM)–amino acid] and [Cu(ATSM)–octreotide] conjugates

Abstract

Two new bifunctional chelators that are derivatives of the bis(thiosemicarbazone) ATSMH₂ proligand have been prepared, one with two phenyl carboxylate substituents on the exocyclic nitrogens (L¹H₂) and one with a single phenyl carboxylate (L²H₂). The new ligands have been characterised by NMR spectroscopy, mass spectrometry and in the case of L¹H₂ by X-ray crystallography. The copper, nickel and zinc complexes of the new ligands have been synthesised and characterised. Electrochemical measurements show that the copper(II) complexes undergo a reversible reduction attributable to a Cu(II)/Cu(I) process. The new proligands have been tethered to the N-α-Boc-protected amino acids lysine and ornithine using solution and solid phase methods. The new amino acid conjugates form copper complexes and the complexes have been characterised by mass spectrometry and electronic spectroscopy. The bifunctional chelator L²H₂ has been conjugated to the tumour targeting peptide octreotide and the new ATSMH₂–octreotide conjugate and its copper complex have been characterized by mass spectrometry. These new systems have the potential to be used for new targeted copper radiopharmaceuticals for imaging and therapy.