Structural trends in copper(<scp>ii</scp>) bis(thiosemicarbazone) radiopharmaceuticals

Blower, Philip J.; Castle, Thomas C.; Cowley, Andrew R.; Dilworth, Jonathan R.; Donnelly, Paul S.; Labisbal, Elena; Sowrey, Frank E.; Teat, Simon J.; Went, Michael J.

doi:10.1039/b307499d

Cited by 138 publications

(114 citation statements)

References 32 publications

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“…[46] Weighted root-mean-square deviations (RMSD) calculated for all nonhydrogen atoms, between the X-ray crystal structures and the DFT optimised gas-phase geometries are typically < 0.22 .…”

Section: Resultsmentioning

confidence: 99%

“…[42][43][44][45] X-ray crystal structures for 1 to 6 have also been reported. [46] All complexes have been characterised by elemental analysis, high-resolution mass spectrometry, reverse-phase gradient HPLC, UV/Vis spectroscopy, X-band EPR spectroscopy, cyclic voltammetry and DFT calculations. [40] Complexes 7-9 were prepared in accordance with the procedures described by Gannon et al [47] and the X-ray crystal structure of complex 7 is shown in Figure 1.…”

Section: Resultsmentioning

confidence: 99%

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Spectroelectrochemical and Computational Studies on the Mechanism of Hypoxia Selectivity of Copper Radiopharmaceuticals

Holland

Barnard

Collison

et al. 2008

Chemistry A European J

128

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Detailed chemical, spectroelectrochemical and computational studies have been used to investigate the mechanism of hypoxia selectivity of a range of copper radiopharmaceuticals. A revised mechanism involving a delicate balance between cellular uptake, intracellular reduction, reoxidation, protonation and ligand dissociation is proposed. This mechanism accounts for observed differences in the reported cellular uptake and washout of related copper bis(thiosemicarbazonato) complexes. Three copper and zinc complexes have been characterised by X-ray crystallography and the redox chemistry of a series of copper complexes has been investigated by using electronic absorption and EPR spectroelectrochemistry. Time-dependent density functional theory (TD-DFT) calculations have also been used to probe the electronic structures of intermediate species and assign the electronic absorption spectra. DFT calculations also show that one-electron oxidation is ligand-based, leading to the formation of cationic triplet species. In the absence of protons, metal-centred one-electron reduction gives the reduced anionic copper(I) species, [CuIATSM](-), and for the first time it is shown that molecular oxygen can reoxidise this anion to give the neutral, lipophilic parent complexes, which can wash out of cells. The electrochemistry is pH dependent and in the presence of stronger acids both chemical and electrochemical reduction leads to quantitative and rapid dissociation of copper(I) ions from the mono- or diprotonated complexes, [CuIATSMH] and [Cu(I)ATSMH2]+. In addition, a range of protonated intermediate species have been identified at lower acid concentrations. The one-electron reduction potential, rate of reoxidation of the copper(I) anionic species and ease of protonation are dependent on the structure of the ligand, which also governs their observed behaviour in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Spectroelectrochemical and Computational Studies on the Mechanism of Hypoxia Selectivity of Copper Radiopharmaceuticals

Holland

Barnard

Collison

et al. 2008

Chemistry A European J

128

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“…Hypoxia selectivity, quantified by the "hypoxia selectivity index", HSI [72,77], can be controlled via alkylation of the diketone backbone, while other properties important to optimizing imaging quality or cell uptake (lipophilicity, serum protein binding, membrane permeability, detailed structural parameters etc. [78]) can be controlled by alkylation of the terminal amino groups (Table 1). There is also a possibility to alter the donor atoms to control redox potential [79].…”

Section: Copper Bis(thiosemicarbazone) Complexes (Btscs)mentioning

confidence: 99%

PET imaging of cardiac hypoxia: Opportunities and challenges

Handley¹,

Medina²,

Nagel

et al. 2011

Journal of Molecular and Cellular Cardiology

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Myocardial hypoxia is a major factor in the pathology of cardiac ischemia and myocardial infarction. Hypoxia also occurs in microvascular disease and cardiac hypertrophy, and is thought to be a prime determinant of the progression to heart failure, as well as the driving force for compensatory angiogenesis. The non-invasive delineation and quantification of hypoxia in cardiac tissue therefore has the potential to be an invaluable experimental, diagnostic and prognostic biomarker for applications in cardiology. However, at this time there are no validated methodologies sufficiently sensitive or reliable for clinical use. PET imaging provides real-time spatial information on the biodistribution of injected radiolabeled tracer molecules. Its inherent high sensitivity allows quantitative imaging of these tracers, even when injected at subpharmacological (≥pM) concentrations, allowing the non-invasive investigation of biological systems without perturbing them. PET is therefore an attractive approach for the delineation and quantification of cardiac hypoxia and ischemia. In this review we discuss the key concepts which must be considered when imaging hypoxia in the heart. We summarize the PET tracers which are currently available, and we look forward to the next generation of hypoxia-specific PET imaging agents currently being developed. We describe their potential advantages and shortcomings compared to existing imaging approaches, and what is needed in terms of validation and characterization before these agents can be exploited clinically.

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“…This neutral Pd II complex crystallizes in the monoclinic C2/c space group with Z = 4 as discrete C 20 H 22 N 6 S 2 Pd·DMSO molecules. On the basis of other α-diketone bis(thiosemicarbazones), [15] the mode of coordination for this complex is as expected; two iminic nitrogen atoms and two thiolato sulfur atoms bond to Pd on the loss of the hydrogen atoms of N2 and N2A from both thiosemicarbazone moieties to give an approximately planar, four-coordinate complex. Thus, the coordination of the bis(thiosemicarbazone) results in the formation of three five-membered chelate rings (PdSCNN, PdNCCN and PdNNCS).…”

Section: Synthesis and Structure Of The Complex [Pd(bbtsc)]mentioning

confidence: 99%