Browsing by Author "Hambley, TW"

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    Radiosynthesis and ‘click’ conjugation of ethynyl‐4‐[18F]fluorobenzene — an improved [18F]synthon for indirect radiolabeling
    (John Wiley and Sons, 2015-11-03) Roberts, MP; Pham, TQ; Doan, J; Jiang, CD; Hambley, TW; Greguric, I; Fraser, BH
    Reproducible methods for [18F]radiolabeling of biological vectors are essential for the development of new [18F]radiopharmaceuticals. Molecules such as carbohydrates, peptides and proteins are challenging substrates that often require multi-step indirect radiolabeling methods. With the goal of developing more robust, time saving, and less expensive procedures for indirect [18F]radiolabeling of such molecules, our group has synthesized ethynyl-4-[18F]fluorobenzene ([18F]2, [18F]EYFB) in a single step (14 ± 2% non-decay corrected radiochemical yield (ndc RCY)) from a readily synthesized, shelf stable, inexpensive precursor. The alkyne-functionalized synthon [18F]2 was then conjugated to two azido-functionalized vector molecules via CuAAC reactions. The first ‘proof of principle’ conjugation of [18F]2 to 1-azido-1-deoxy-β-d-glucopyranoside (3) gave the desired radiolabeled product [18F]4 in excellent radiochemical yield (76 ± 4% ndc RCY (11% overall)). As a second example, the conjugation of [18F]2 to matrix-metalloproteinase inhibitor (5), which has potential in tumor imaging, gave the radiolabeled product [18F]6 in very good radiochemical yield (56 ± 12% ndc RCY (8% overall)). Total preparation time for [18F]4 and [18F]6 including [18F]F− drying, two-step reaction (nucleophilic substitution and CuAAC conjugation), two HPLC purifications, and two solid phase extractions did not exceed 70 min. The radiochemical purity of synthon [18F]2 and the conjugated products, [18F]4 and [18F]6, were all greater than 98%. The specific activities of [18F]2 and [18F]6 were low, 5.97 and 0.17 MBq nmol−1, respectively. © 2015 John Wiley & Sons, Ltd.
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    Radiosynthesis of [18F]-ethynyl-4-fluorobenzene for click conjugation
    (John Wiley & Sons, Inc, 2013-05-09) Roberts, MP; Pham, TQ; Doan, J; Fraser, BH; Hambley, TW; Greguric, I
    Objectives: Fluorine-18 is the most commonly utilised PET nuclide due to its favourable characteristics including 110 min half-life, low positron energy and ease of availability. Unfavourable harsh reaction conditions required for direct labelling have led to the development of indirect labelling methods; including the use of the alkyne-azide copper(I) catalysed cycloaddition (CuAAC) ‘click’ reaction. We have investigated the one-step radiolabelling of a suitable precursor, 4-ethynyl-N,N,N-trimethylbenzenaminium triflate (1), particularly to probe the usefulness of the trimethylammonium leaving group, and developed a novel [18F]-alkynyl synthon (2) that has successfully been conjugated to an azido-sugar (3, R1) and azido-peptide mimetic (3, R2). Methods: Radiosynthesis (Figure 1) was achieved by reacting 4-ethynyl-N,N,N-trimethylbenzenaminium triflate (1) with activated K18F.K222 complex, in DMF at 150 °C for 5 minutes, via standard nucleophilic substitution, following HPLC purification to afford [18F]-ethynyl-4-fluorobenzene (2). The collected [18F]-synthon (2) was concentrated by passing through a reverse phase C18 Sep-Pak® Plus cartridge and then standard click reaction conditions were utilised by first eluting the [18F]-synthon with acetonitrile into a reaction vial containing copper(I) iodide, sodium ascorbate, lutidine and the azido derivative of choice in a water/acetonitrile mixture. The reaction was heated at 85 °C for 10 minutes and purified by HPLC to obtain the clicked derivative (3). FNNNNOTfF18H18FK222, K2CO3DMF, 150 °C,5 minazido-RCuINa-ascorbatelutidineACN/H2O 50%80 °C, 10 min18ROHNHOOHOHNONHR2=R1=OHOOHHOOH(1)(2)(3) Results: 4-Ethynyl-N,N,N-trimethylbenzenaminium triflate (1) was successfully labelled in 15-20% yield (non-decay corrected) after HPLC purification. In attempt to by-pass purification by HPLC a C18 Sep-Pak® was also attempted, however the decreased purity obtained resulted in decreased conjugation yields. The reasonably low yield of [18F]-ethynyl-4-fluorobenzene (2) is attributed to the competing [18]F-substitution on the trimethyl ammonium group forming [18F]-methylfluoride rather than the desired aromatic labelling. The alkynyl synthon (2) was successfully conjugated to 2 small molecules (a sugar and a peptide mimetic) using traditional CuAAC conditions. Conclusions: We have synthesised a new [18F]-labelled alkynyl synthon that was successfully clicked to two azido derivatives in adequate yield. Future work involves modification of the synthon with more activating substituents to decrease the competing [18F]-methylfluoride production and consequently increase the desired click conjugation yield. In addition we intend to further investigate other forms of cartridge purification. © 2013 John Wiley & Sons, Ltd.
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    Stabilization of triam(m)inechloridoplatinum complexes by oxidation to PtIV.
    (CSIRO Publishing, 2011-03-11) Daly, HL; Hall, MD; Failes, TW; Zhang, M; Foran, GJ; Hambley, TW
    PtIV analogues of the active end groups {PtClN3} of multinuclear Pt anticancer drugs have been investigated. The crystal structure of trans,mer-[PtCl(OH)2(dien)]Cl shows that the bond lengths are similar to those in the dihydroxidoplatinum(iv) analogue of cisplatin. The axial ligands are shown to be the predominant influence on reduction potentials with the dihydroxido complex trans,mer-[PtCl(OH)2(NH3)3]Cl being the most resistant to reduction. X-ray absorption near-edge spectroscopy is shown to be suitable for monitoring the oxidation state of these complexes and reveals that trans,mer-[PtCl(OH)2(NH3)3]+ survives for more than 2 h in cancer cells. © 2011, CSIRO Publishing
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    Using XANES to monitor the oxidation state of cobalt complexes
    (CSIRO Publishing, 2007-02-14) Hall, MD; Underwood, CK; Failes, TW; Foran, GJ; Hambley, TW
    X-Ray absorption near-edge structure (XANES) spectroscopy was used to monitor the oxidation state of cobalt following treatment of Co-III complexes with reducing agents such as ascorbate and cysteine. It was established that the XANES spectra of mixtures of Co-II and Co-III complexes can be used to calculate proportions of the two oxidation states by monitoring the height of the Co K-edge. The relationships developed were used to estimate proportions of each complex in solutions of Co-III complexes treated with reducing agents. © 2007, CSIRO Publishing