Versatile new bis(thiosemicarbazone) bifunctional chelators: synthesis, conjugation to bombesin(7-14)-NH(2), and copper-64 radiolabeling.
ABSTRACT New bifunctional derivatives of diacetyl-bis(4-methylthiosemicarbazone) (H(2)atsm) have been prepared by a selective transamination reaction of a new dissymmetric bis(thiosemicarbazone) precursor H(2)L(1). The new derivatives contain an aliphatic carboxylic acid (H(2)L(2) and H(2)L(3)), t-butyl carbamate (H(2)L(4)), or ammonium ion (H(2)L(5)) functional group. The new ligands and copper(II) complexes have been characterized by NMR spectroscopy, mass spectrometry, and microanalysis. The complex Cu(II)(L(4)) was structurally characterized by X-ray crystallography and shows the metal center to be in an N(2)S(2) distorted square planar coordination geometry. Electrochemical measurements show that the copper(II) complexes undergo a reversible reduction attributable to a Cu(II)/Cu(I) process. The ligands and the copper(II) complexes featuring a carboxylic acid functional group have been conjugated to the tumor targeting peptide bombesin(7-14)-NH(2). The bifunctional peptide conjugates were radiolabeled with copper-64 in the interest of developing new positron emission tomography (PET) imaging agents. The conjugates were radiolabeled with copper-64 rapidly in high radiochemical purity (>95%) at room temperature under mild conditions and were stable in a cysteine and histidine challenge study.
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ABSTRACT: The three mammalian bombesin (Bn) receptors (gastrin-releasing peptide [GRP] receptor, neuromedin B [NMB] receptor, BRS-3) are one of the classes of G protein-coupled receptors that are most frequently over-express/ectopically expressed by common, important malignancies. Because of the clinical success of somatostatin receptor-mediated imaging and cytotoxicity with neuroendocrine tumors, there is now increasing interest in pursuing a similar approach with Bn receptors. In the last few years then have been more than 200 studies in this area. In the present paper, the in vitro and in vivo results, as well as results of human studies from many of these studies are reviewed and the current state of Bn receptor-mediated imaging or cytotoxicity is discussed. Both Bn receptor-mediated imaging studies as well as Bn receptor-mediated tumoral cytotoxic studies using radioactive and non-radioactive Bn-based ligands are covered.Current Drug Delivery 11/2010; 8(1):79-134.
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ABSTRACT: The reaction of nickel(II), copper(II) chlorides and cadmium(II) chloride and bromide with thiophene-2,3-dicarboxaldehyde bis(thiosemicarbazone) (2,3BTSTCH2) leads to a series of new complexes: [Ni(2,3BTSTCH)]Cl, [Cu(2,3BTSTC)], [CdCl2(2,3BTSTCH2)] and [CdBr2(2,3BTSTCH2)]. The crystal structures of the ligand and of [Ni(2,3BTSTCH)]Cl complex have been determined. In this case, we remark an unusual non-symmetrical coordination mode for the two functional groups: one acting as a thione and the second as a deprotonated thiolate. All compounds have been tested for their antifungal activity against human pathogenic fungi: Candida albicans, Candida glabrata and Aspergillus fumigatus, the cadmium complexes exhibit the highest antifungal activity. Cytotoxicity was evaluated using two biological methods: human MRC5 cultured cells and brine shrimp Artemia salina bioassay.Journal of inorganic biochemistry 05/2013; 126C:76-83. · 3.25 Impact Factor
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ABSTRACT: Dysregulation of apoptosis and necrosis is central to many diseases and non-invasive imaging of cell death is an important clinical objective to stage disease or to monitor treatment progress. The C2A domain of rat synaptotagmin I binds to phosphatidylserine (PS) exposed during cell death and modification to its lysine residues has been shown to disrupt PS binding. Site-specifically labelled (99m)Tc(CO)3-C2AcH and (68)Ga-C2Ac have previously been investigated for single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging, respectively. We wished to design a (64)Cu-labelled counterpart due to the longer half-life of (64)Cu. Since the calcium binding sites in C2A may interfere with copper binding we sought a high affinity, fast labelling chelator. We synthesised a maleimide functionalised bis(thiosemicarbazone), H2ATSE/AMal, for the site-specific copper-64 radiolabelling of thiol-functionalised C2Ac. When radiolabelling was performed by incubation of the ligand-protein conjugate (post-labelling approach), analysis of the resultant (64)CuATSE/AMal-C2Ac revealed that the C2Ac was able to compete for radiocopper with the chelator. In contrast, the pre-labelled (64)CuATSE/AMal-C2Ac conjugate revealed good stability in serum and maintained target affinity in a red blood cell binding assay. The results suggest that due to the intrinsic copper binding properties of the protein, a pre-labelling approach is preferred for the C2Ac domain of synaptotagmin I when copper is the desired radioisotope.Journal of inorganic biochemistry 07/2013; 128C:108-111. · 3.25 Impact Factor