Browsing by Author "Doan, J"

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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.