Rhenium complexation‐dissociation strategy for fluorine‐18 labelling of bidentate PET ligands

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John Wiley & Sons, Inc
Objectives Pursuant to the discovery that rhenium complexation promotes fluorine‐18 radiolabelling of 1,10‐phenanthroline systems under low temperature, quasi‐aqueous conditions, which circumvent the need for azeotropic drying, we expanded our investigation towards thermal decomplexation strategies to improve the radiosynthesis of similar pyridinyl bidentate tracers. Methods Thirty‐eight compounds were synthesised based upon chloro, bromo, nitro, and fluoro substitutions of 1,10‐ phenanthroline, 2,2’‐bipyridine and 8‐hydroxyquinoline structures and their respective rhenium tricarbonyl chloride complexes. Each of these compounds, save for the nonradioactive fluoro substituted standards, were reacted (>n = 8) under microfluidic conditions with tetraethyl ammonium [18F]fluoride in anhydrous DMSO solvent with increasing reaction temperatures ranging from 50°C to 190°C in 20°C increments. All other parameters such as the precursor quantity, radioactivity, and flow rate/reaction time were kept constant (0.08 μmol, 29 ± 10 MBq, 20 μL·min−1/47 s, respectively). Radiochemical yields (RCYs) for each reaction were then calculated from the Radio‐HPLC peak integrations of the non‐isolated products. Results High RCYs were observed for the [18F]fluoride substitution of rhenium complexed 1,10‐phenanthroline structures (up to 91%) at temperatures ≤90°C, which could prove useful as a novel method for producing PET‐optical tracers given the optical emission properties of rhenium. Good RCYs were also observed for the 2,2’‐bipyridine rhenium complexes, peaking at 84% at 130°C in one example, which then dissociated to form the radiolabelled ligand in 82% RCY at a higher temperature of 190°C, as shown in Figure 1. Radiolabelling of these ligands was unsuccessful under conventional conditions using dry [18F]fluoride, thus establishing rhenium complexation‐dissociation as a novel method for radiolabelling. The fluorine‐18 labelling of 8‐ hydroxyquinoline structures was also tested as a means of improving the radiosynthesis of Alzheimer's disease imaging PET tracers such as [18F]CABS13. While preliminary rhenium complexation‐dissociation experiments have not yet improved on the radiosynthesis of [18F]CABS13 (5% RCY of ligand & 18% RCY of rhenium complex vs 19±5% RCY of ligand in literature), such experiments have enabled the radiosynthesis of related structures, which could not be radiolabelled under conventional conditions using dry [18F]fluoride (eg, [18F]5‐ fluoro‐8‐hydroxyquinoline). Conclusions We report a novel radiofluorination method utilising the rhenium complexation of pyridinyl bidentate structures. This method facilitates radiolabelling of certain analogues of 2,2’‐bipyridine and 8‐hydroxyquinoline structures, which do not radiolabel under conventional conditions. Investigations into monopyridine structures and the development of milder methods of decomplexation are currently ongoing. © 2019 The Authors
Volume 62, Supplement 1 of the Journal of Labelled Compounds & Pharmaceuticals is comprised of the Abstracts from ISRS 2019.
Rhenium, Dissociation, Fluorine 18, Labelling, Ligands, Positron computed tomography
Klenner, M., Pascali, G., Zhang, B., Massi, M., & Fraser, B. (2019). Rhenium complexation‐dissociation strategy for fluorine‐18 labelling of bidentate PET ligands. Poster presented at the 23rd International Symposium on Radiopharmaceutical Sciences (ISRS 2019), Beijing, China, 26 to 31 May, 2019. In Journal of Labelled Compounds and Radiopharmaceuticals, 62 (S1), S198- S199. doi:10.1002/jlcr.3725.