Browsing by Author "Holland, JP"

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    Alternative approaches for PET radiotracer development in Alzheimer's disease: imaging beyond plaque
    (Wiley, 2013-12-11) Holland, JP; Liang, SH; Rotstein, BH; Collier, TL; Stephenson, NA; Greguric, I; Vasdev, N
    Alzheimer's disease (AD) and related dementias show increasing clinical prevalence, yet our understanding of the etiology and pathobiology of disease-related neurodegeneration remains limited. In this regard, noninvasive imaging with radiotracers for positron emission tomography (PET) presents a unique tool for quantifying spatial and temporal changes in characteristic biological markers of brain disease and for assessing potential drug efficacy. PET radiotracers targeting different protein markers are being developed to address questions pertaining to the molecular and/or genetic heterogeneity of AD and related dementias. For example, radiotracers including [11C]-PiB and [18F]-AV-45 (Florbetapir) are being used to measure the density of Aβ-plaques in AD patients and to interrogate the biological mechanisms of disease initiation and progression. Our focus is on the development of novel PET imaging agents, targeting proteins beyond Aβ-plaques, which can be used to investigate the broader mechanism of AD pathogenesis. Here, we present the chemical basis of various radiotracers which show promise in preclinical or clinical studies for use in evaluating the phenotypic or biochemical characteristics of AD. Radiotracers for PET imaging neuroinflammation, metal ion association with Aβ-plaques, tau protein, cholinergic and cannabinoid receptors, and enzymes including glycogen-synthase kinase-3β and monoamine oxidase B amongst others, and their connection to AD are highlighted. Copyright © 2013 John Wiley & Sons, Ltd.
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    Computational studies on hypervalent iodonium(III) compounds as activated precursors for 18F radiofluorination of electron-rich arenes
    (Elsevier B.V., 2015-08-15) Hill, DE; Holland, JP
    Fluorination of deactivated and non-activated electron-rich arenes via nucleophilic aromatic substitution (SNAr) reactions represents a major challenge in medicinal and radiochemistry. In efforts to activate electron-rich arenes for facile synthesis of fluoroarenes, a wide range of reagents have been developed. In particular, aryliodonium(III) species (salts and ylides) show promise as reagents for synthesising 18F-radiolabelled molecules for use in positron emission tomography (PET). However, in fluorination reactions involving a reductive elimination mechanism, aryliodonium(III) reagents present two competing pathways that lead to product (via transition state 1 (TS1)) or by-product (TS2) formation. Here, we present detailed computational studies using Density Functional Theory (DFT) methods on the relatively stability of these competing transition states and present an analysis based on transition state theory that allows prediction of chemoselectivity in aryliodonium(III) fluorination reactions. The methods developed indicate that the calculated difference in free energy (ΔΔG‡) and the calculated equilibrium constant (ln K‡) between the two transition states are chemically accurate molecular descriptors of chemoselectivity in aryliodonium(III) fluorination. It is anticipated that the tools developed here will aid design of the next generation of reagents with increased chemoselectivity for fluorination and radiofluorination of electron-rich arenes. © 2015 Elsevier B.V.
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    Evaluating the accuracy of density functional theory for calculating 1H and 13C NMR chemical shifts in drug molecules
    (Elsevier B.V., 2015-01-01) Hill, DE; Vasdev, N; Holland, JP
    The accuracy of different DFT methodologies for calculating 1H and 13C NMR chemical shifts in (R)-ispinesib, a complex drug molecule with multiple chemical groups and one stereocentre, has been evaluated. The accuracy of 6 basis sets and 16 different XC functionals was tested. In addition, we present a detailed study on the role of geometry optimisation (in gas and solution phase using a chloroform polarisable continuum model) on the accuracy of the calculated NMR spectra. NMR calculations using the double-ζ basis sets DGDZVP and 6-31++G(d,p) were found to be more accurate (and computationally more efficient) than those using larger triple-ζ basis sets. The O3LYP/DGDZVP methodology in solution phase using a geometry optimised at the same level of theory was found to be the most accurate method with mean absolute errors (MAEs) for 1H and 13C chemical shifts of 0.174 ppm and 3.972 ppm, respectively. Irrespective of the choice of XC or basis set used, complete geometry optimisation in either gas or solvent phase was found to be essential for attaining the highest accuracy in both 1H and 13C calculated chemical shifts. Finally, the role of molecular conformation was examined by calculating the Boltzmann-weighted 1H and 13C chemical shifts. Overall, we demonstrate that DFT shows exceptional promise for use in calculating the NMR chemical shifts in complex drug molecules. In the future, DFT calculations of NMR parameters are set to play an increasingly important role in drug discovery and chemical optimisation. © 2014 Elsevier B.V.