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Development of (S)-[18F]T1 as first PET tracer for imaging the α3β4 nicotinic acetylcholine receptor

Sarasamkan, J.; Fischer, S.; Deuther-Conrad, W.; Scheunemann, M.; Ludwig, F.-A.; Vajragupta, O.; Brust, P.
Neuronal nicotinic acetylcholine receptors (nAChRs) are composed of diverse subtypes which have different functional properties, distributions and pharmacological profiles. The α7, α3β4 and α4β2 nAChRs are well recognized as drug targets implicated in cognitive disorders and addiction. Therefore, to image nAChRs in vivo, subtype-selective radiotracers need to be developed.
A novel PET radiotracer for imaging nAChRs was developed based on the design and synthesis of six racemates (T1-T6) and its enantiomers based on the structure of triazole-quinuclidine QND8. All R enantiomers were found to be selective to α7 nAChR while their S counterparts were selective to α3β4 nAChR. (S)-T1 binds selectively to α3β4 nAChR (Ki 3.09 nM) with very modest off-target binding to α1 receptor, dopamine receptors and serotonin receptors. Radiosynthesis of (S)-[18F]T1 was achieved by two-step reaction, starting with the preparation of 18F-alkyne synthon (1-ethynyl-4-[18F]fluorobenzene; [18F]2), followed by the click reaction between [18F]2 and (S)-azidoquinuclidine.
The radiosynthesis of (S)-[18F]T1 was achieved in 130 min with the overall isolated radiochemical yield of 4.3±1.3%, radiochemical purity > 99%, and molar radioactivity > 158 GBq/µmol at end of synthesis. The brain uptake and brain-to-blood ratio of this tracer in mice at 30 min after injection were 6.06% ID/g and 6.1, respectively. The tracer remained intact > 99% in brain homogenates. Only one major radiometabolite was detected in plasma and urine samples. In vitro autoradiography on pig brain slices revealed high binding of (S)-[18F]T1 to brain regions consistent with the α3β4 nAChR distribution. Selective binding of (S)-[18F]T1 was evidenced by (i) the reduction of percent labeling of this tracer in the presence of a selective α3β4 nAChR partial agonist, AT-1001 and (ii) the retention of the tracer in the presence of α7 nAChR-specific SSR180711.
These findings suggest the potential of (S)-[18F]T1 for imaging the α3β4 nAChR in the brain as a promising tool for both diagnosis and therapy monitoring of neurodegenerative diseases and addiction.
This work was supported by Thailand Research Fund (TRF) through the Royal Golden Jubilee Ph.D. Program (grant no. PHD/0272/2552) to J.S. and O.V.
[1] K. Arunrungvichian, V. V. Fokin, O. Vajragupta, P. Taylor. ACS Chem Neurosci. 2015, 6, 1317-1330.
[2] J. Sarasamkan, M. Scheunemann, N. Apaijai, S. Palee, W. Parichatikanond, K. Arunrungvichian, et al. ACS Med. Chem. Lett. 2016, 7, 890- 895.
  • Open Access Logo Abstract in refereed journal
    Journal of Labelled Compounds and Radiopharmaceuticals 60(2017)S1, S50
    DOI: 10.1002/jlcr.3507

Publ.-Id: 25854