Radiosynthesis of a [¹⁸F]-quinuclidine 1,2,3-thiazole derivative as PET radioligand for neuroimaging of the α7 nicotinic acetylcholine receptor

Aim
The α7 nicotinic acetylcholine receptor (α7nAChR) is well recognized as a key receptor involved in memory formation and cognition which implicates its involvement in the pathophysiology of neurodegenerative disorders. Currently, this receptor subtype is one of the most attractive targets for neuroimaging to monitor the etiology and progression of brain diseases such as schizophrenia and Alzheimer’s disease (AD). Therefore, a new PET radioligand selective to α7nAChR was developed in this study. The structure of the developed ligand is based on a novel potent and selective α7nAChR agonist, 3-(4-hydroxyphenyl-1,2,3-triazol-1-yl) quinuclidine (QND8) which demonstrated cognitive enhancement in mice [1].
Materials and methods
The structure of the radioligand (¹⁸F-QND) was modified from QND8 by replacing the hydroxyl (OH) group with fluorine. After synthesis of the starting quinuclidine azide and aryl alkyne, F-QND and its precursor were synthesized by copper-catalyzed azide-alkyne cycloaddition (CuAAC) or click chemistry. Their structures were confirmed by ¹H-NMR, ¹³C-NMR and mass spectrometry (MS). ¹⁸F-QND was radiolabeled by nucleophilic substitution of the nitro precursor. Altered amounts of kryptofix and various conditions (solvent and temperature) were chosen to improve the radiolabeling yield. The radiolabeled compound was separated and purified by chromatography. The radiochemical yield and radiochemical purity were analyzed by radio-thin layer chromatography and radio-high performance liquid chromatography. Non-radioactive references were used to confirm the stereochemistry of the nitro-precursor and F-QND.
Results
The chemical yields of the nitro-precursor (NO₂-QND) and the reference standard (F-QND) were 21% and 11%, respectively, with purity higher than 95%. The radiolabeling yield of ¹⁸F-QND was 7% with radiochemical purity > 98% and specific activity of 65 GBq/µmol. The stereochemistry study approved that both compounds were optically active. Therefore, the developed radiochemical processes can be applied for the radiosynthesis of further ¹⁸F-QND-derivatives.
Conclusion
Radiosynthesis of ¹⁸F-QND was accomplished by nucleophilic substitution of the phenyl-nitro compound. However, at high temperature racemization currently cannot be excluded.
References
1. Chalon S, Guilloteau D, PIN F, Routier S, Suzenet F, Vercouillie J. Centre National De La Recherche Scientifique (C.N.R.S). Patent WO2012143526A1, Oct. 6, 2012.