Authors: Igor Camargo Fontana1,3, Salvatore Bongarzone1,2, Eduardo Zimmer3, Diogo Onofre de Souza3, Antony Gee1,2
1Division of Imaging Sciences and Biomedical Engineering, King's College London, 4th Floor, Lambeth Wing, St Thomas' Hospital, London SE1 7EH, United Kingdom.
2PET Imaging Centre Facility, St Thomas’ Hospital, London SE1 7EH, United Kingdom.
3Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Background
Astrocyte glutamate transporter 1 (GLT-1) dysfunction is implicated in several neurodegenerative diseases1. Selective GLT-1 inhibitors2 bear a carboxylic acid which would lead to low brain penetrance. PET imaging would allow to study the in vivo brain penetration of carboxylic acid and their derivatives (e.g. esters).
Aims
The aim of this work is to develop the carbon-11 labelled pro-radiotracer ([11C]IF1) which we hypothesize will be hydrolysed to the GLT-1-targeting radiotracer ([11C]IF2 – Fig 1B) after passage across the BBB (Fig 1C).
Methods
Eckert & Ziegler Modular-Lab system was implemented for [11C]IF1 radiosynthesis. [11C]CO2 to [11C]CO conversion followed the silane lithium derivative strategy3. The [11C]CO afforded [11C]IF0 via a palladium-mediated [11C]carbonylation reaction (Fig 1D). [11C]IF1 was obtained after BOC deprotection with trifluoroacetic acid (90 ̊C, 4 min).
Results and Conclusion
Crude [11C]IF1 was obtained within 18 min after the end of bombardment with radiochemical yield of 8% (decay corrected) based on radio-HPLC, with a radiochemical purity of 99% after reformulation. [11C]IF1, a potential GLT-1 pro-radiotracer, was successfully synthesized from [11C]CO. Low brain uptake was observed in mouse receiving [11C]IF1 intravenously.
References
1. Peterson AR. et al. Post-translational Regulation of GLT-1 in Neurological Diseases and Its Potential as an Effective Therapeutic Target. Front Mol Neurosci. 2019;12(164).
2. Greenfield A. et al. Synthesis and biological activities of aryl-ether-, biaryl-, and fluorene-aspartic acid and diaminopropionic acid analogs as potent inhibitors of the high-affinity glutamate transporter EAAT-2. Bioorg Med Chem Lett. 2005;15(22).
3. Taddei C. et al. [(11)C]CO2 to [(11)C]CO conversion mediated by [(11)C]silanes: a novel route for [(11)C]carbonylation reactions. Chem Commun (Camb). 2015;51(59).