Radiosynthesis of [18F]-ethynyl-4-fluorobenzene for click conjugation
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Date
2013-05-09
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John Wiley & Sons, Inc
Abstract
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.
Description
Volume 56, Supplement 1 of the Journal of Labelled Compounds & Radiopharmaceuticals is comprised of the abstracts from the 20th International Symposium on Radiopharmaceutical Sciences.
Keywords
Sodium, Fluorine 18, Copper iodides, Azido compounds, Positron computed tomography, Labelling
Citation
Roberts, M., Tien, P., Doan, J., Fraser, B., Hambley, T. & Greguric, I. (2013). Radiosynthesis of [F-18]-ethynyl-4-fluorobenzene for click conjugation. Poster presented at the 20th International Symposium on Radiopharmaceutical Sciences, Jeju, South Korea, May 12-17, 2013. In Journal of Labelled Compounds and Radiopharmaceuticals, 56, (S1), S178. doi:10.1002/jlcr.3058