Development of a PET ligand for imaging PDE10A in brain - synthesis, potency, metabolism and radiochemistry of a 7-(2-fluoroethoxy)-6-methoxy-quinazoline derivative


Development of a PET ligand for imaging PDE10A in brain - synthesis, potency, metabolism and radiochemistry of a 7-(2-fluoroethoxy)-6-methoxy-quinazoline derivative

Schwan, G.; Funke, U.; Deuther-Conrad, W.; Egerland, U.; Birkemeyer, C.; Scheunemann, M.; Nieber, K.; Sträter, N.; Brust, P.; Briel, D.

The phosphodiesterase (PDE) 10A plays an important role in neurotransmission by regulating intracellular levels of the cyclic nucleotides cAMP and cGMP in dopaminergic neurons. In consequence, PDE10A is associated with dopamine-related central nervous diseases such as Huntington’s disease and schizophrenia. Thus, PDE10A is a promising candidate for drug development with a variety of selective PDE10A inhibitors published during the last decade [1, 2]. The aim of the presented work is the development of a positron emission tomography (PET)
radiotracer for imaging of PDE10A in vivo.
Based on a lead structure (IC50PDE10A = 8 nM), published for therapeutic applications [3], three nonradioactive fluoroalkoxy derivatives (1, 2, 3) were enantioselectively synthesized over 11-14 steps and characterized regarding their potency and selectivity to inhibit PDE10A in a cAMP competition assay. Prolongation of the alkyl chain from 1 to 3 by one methylene group each resulted in decreased inhibitory potency from IC50 = 24 nM over 106 nM to 144 nM. Metabolic stability of 2 was determined in comparison to the lead compound in an in-vitro metabolism assay using rat liver S9-fractions. Metabolites were structurally characterized using ESI-MS-MS coupling techniques.
With regard to radiochemical accessibility, derivative 2 appeared as the most promising candidate for radioligand investigation. Initially, a two-step synthesis of [18F]2, consisting of 18F-labelling of 1,3-bistosyloxyethane and following coupling with phenolic precursor 4, was carried out. For the 18F-fluoroalkylation step labeling yields (LY) of 30-45% were achieved. Consequently, in a one-step procedure the tosylethoxy precursor 5 was used for 18Flabelling, improving LY up to 42-72%. Biodistribution studies in female CD-1 mice revealed high initial brain uptake of [18F]2. However, it was not significantly inhibited by competition with 2 or by pre-treatment with MP-10, a high PDE10A specific inhibitor, indicating lack of specificity in vivo. In conclusion, these results motivate for further structural variation of the lead compound to make it suitable for neuroimaging of PDE10A with PET.
Acknowledgements: We would like to thank J. Ortwein (Institute of Pharmacy, University of Leipzig) and the team of L. Hennig (Institute for Analytical Chemistry, University of Leipzig) for their analytical support. This project was financed by resources of the European Fond for Regional Development (EFRE) and the Free State of Saxony.
References:
1. Chappie et al., Current Opinion in Drug Discovery & Development 2009, 12, 458–467.
2. Kehler and J. P. Kilburn, Expert Opinion on Therapeutic Patents 2009, 19, 1715–1725.
3. Chappie et al., J. Med. Chem. 2006, 50, 182–185.

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    Joint Meeting of the Austrian and German Pharmaceutical Science, 20.-23.09.2011, Innsbruck, Österreich

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