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) ATSMH(2) proligand have been prepared, one with two phenyl carboxylate substituents on the exocyclic nitrogens (L(1)H(2)) and one with a single phenyl carboxylate (L(2)H(2)). The new ligands have been characterised by NMR spectroscopy, mass spectrometry and in the case of L(1)H(2) 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-alpha-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 L(2)H(2) has been conjugated to the tumour targeting peptide octreotide and the new ATSMH(2)-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.

In Vitro and In Vivo Evaluation of Bifunctional Bisthiosemicarbazone 64Cu-Complexes for the Positron Emission Tomography Imaging of Hypoxia

“…[22][23][24] It has been suggested that complexes that retain the dimethylated backbone are less susceptible to reduction and, thus, more practical for use in delineating hypoxia. 18 To this end, bis(thiosemicarbazones) containing carboxylate 25 and hydrazine groups 26 at the N-terminus have been recently synthesized and conjugated to octreotide and glucose, respectively, though little biological and radiochemical data has been published on these complexes, so it is unknown how these modifications affect their hypoxic selectivity.…”

Applications of “Hot” and “Cold” Bis(thiosemicarbazonato) Metal Complexes in Multimodal Imaging

“…The carboxylic acid functionality was used to attach different peptides, including octreotide, a somatostatin analog with improved pharmacological properties ( Figure 3). [50,51] However, the first in vitro and in vivo study of a functionalized bis(thiosemicarbazone) involved the functionalization of a thiosemicarbazide with an aromatic group bearing different functionalities, such as a hydroxyl, a nitro, or even a nitroimidazol moiety. Some of the examples proved to be hypoxia selective in vitro and in vivo, although with a high liver uptake, pointing to the necessity of opening new directions into the field of functionalization of these compounds, so as to bypass limitations in liver biodistribution.…”

Bis-(thiosemicarbazonato) Zn(ii) complexes as building blocks for construction of supramolecular catalysts

“…71 4.1 Syntheses 4.1.1 Compound 5. It was prepared as described by Cowley et al 43 Thiosemicarbazide 3 (1.00 g, 9.51 mmol) was dissolved in water (17 ml) and treated with 5.5 ml conc. HCl at 10°C in a 100 ml round-bottom flask.…”

“…A typical synthesis protocol consists of two steps: preparation of the ( pro)ligand by condensation of a dicarbonyl compound with two thiosemicarbazide molecules, followed by metallation with an appropriate metal salt. 43,44 Condensation of two different thiosemicarbazides to a dicarbonyl (leading eventually, to dissymmetric M(btsc) complexes), can also be performed, but a good control of reaction conditions during synthesis, is required to avoid formation of unwanted side products. 45 For our syntheses we used a slightly modified synthetic procedure as we did not isolate any of the intermediates.…”

“…This complex was prepared according to procedure described by Cowley et al 43 Compound 8 (253 mg, 2.12 mmol) was dissolved in tetrahydrofurane (THF) and treated with glacial acetic acid (0.2 ml) for ca. 20 min.…”