Ligands for Molecular Imaging: The Synthesis of Bis(thiosemicarbazone) Ligands

Abstract

Bis(thiosemicarbazones) have been of interest to chemists for over fifty years; they display antitumour, antibiotic and antiviral properties. Recently it has become apparent that they may also provide a convenient way of labelling biologically active molecules by using metallic radionuclides and/or fluorescence. Although apparently simple, the synthesis of bis(thiosemicarbazone) ligands can be problematic. This article provides a summary of the published literature, based on the synthetic strategies used and indicates some of the difficulties that may arise.

In Vitro and In Vivo Evaluations of a Hydrophilic 64Cu-Bis(Thiosemicarbazonato)–Glucose Conjugate for Hypoxia Imaging

“…The proligand H 2 -ATSM, Zn-ATSM, and Zn-ATSE/A-G were prepared according to published methods (17)(18)(19)(20).…”

“…64 Cu tracers were produced as described earlier with 64 CuCl 2 provided by The Wolfson Brain Imaging Centre. 18 F-FDG was purchased from PETNET Solutions Ltd.…”

“…Because hypoxia has a profound impact on patient survival (6), methods for the detection and quantification of hypoxia are currently the subject of intense investigation. Several radiolabeled markers have been developed for PET imaging of hypoxia-notably, 18 F-fluoromisonidazole (7)(8)(9) and Cu-diacetyl-bis(N 4 -methylthiosemicarbazone) (Cu-ATSM, where Cu is either 60 Cu, 62 Cu, or 64 Cu) (10,11). 60 Cu-ATSM has been shown to be predictive of radiotherapy treatment outcome in small-scale clinical studies, and 64 Cu-ATSM recently entered clinical trials in the United States (12)(13)(14).…”

“…1, R 1 and R 2 ) (16,17). We have developed methods for the synthesis of Cu-ATSM nonsymmetrically substituted at R 3 and R 4 and have shown that variations in the exocyclic amine substituents have a relatively minor influence on the redox potential of the copper(II) center (18,19) and should not affect hypoxia selectivity. When R 3 or R 4 is a reactive amino group ( Fig.…”

Synthesis, Characterization and X‐ray Structures of [α‐Diphenylethanedione bis(4‐ethylthiosemicarbazonato)]palladium(II) and 1,2,4‐Triazine‐3‐thione–Zinc(II) Complexes Obtained by Metal‐Induced Cyclization

“…[6] It is well known that thiosemicarbazones derived from 1,2-dicarbonyl compounds easily cyclize during the synthesis process, especially when hydroxylic solvents are used or when solutions in such solvents are allowed to crystallize over several days. [7] In all cases, this cyclization leads to 1,2,4-triazine-3-thione ligands (Scheme 1); these ligands are very versatile and are able to form mono-, di-and polynuclear metal complexes as a result of two different coordination modes: as a monodentate, neutral ligand with coordination through the sulfur atom or as an anionic bidentate ligand with coordination through the sulfur and nitrogen atoms. 1 tal containing the open-chain H 2 BbTSC-Et ligand together with the cyclic HTa3T-Et molecules, which are linked to a DMSO molecule by hydrogen bonds.…”