Radioligands for PET Imaging of Cyclic Nucleotide Phosphodiesterases 2A, 5A and 10A (PDE2A, PDE5A, PDE10A)
The enzymes PDE2A, PDE5A and PDE10A belong to the phosphodiesterase superfamiliy and catalyze the cleavage of the cyclic secondary messengers cAMP and cGMP. Thus PDEs terminate intracellular signaling cascades related to various physiological processes. In particular, PDE2A, PDE5A and PDE10A are also involved in neuropathological and cancerous processes and therefore are interesting targets for molecular imaging approaches. Specific PET radioligands for PDE2A, PDE5A and PDE10A would allow the quantification of these enzymes in the human brain and in certain tumors.
In first in vitro autoradiographic experiments the distribution in rat brain of a new, synthesized [18F]fluoroalkylated PDE2A radioligand has been investigated. These studies showed a high and specific accumulation in cortex and striatum and a low uptake in cerebellum, which is consistent with the distribution pattern of PDE2A protein in the brain.
Structure of the new 18F-labeled PDE2A-radiotracers (left) and representative color-coded autoradiographic images of sagittal brain slices (right)
A) in vitro distribution of [18F]TA-I, 60 min p.i. and B) blocking study with addition of 1 µM of a specific PDE2A inhibitor.
Together with our partner of the Université Clermont Auverne (France), we designed and evaluated two differently 18F-labelled PDE5 radioligands based on the same quinoline scaffold. In vitro autoradiographic studies were perfomed on mouse and pig brain slices in order to investigate the target and non-target binding. Biodistribution and radiotracer metabolism were assessed in mice.
As part of our efforts and on basis of dimethoxyquinazoline as lead a novel methoxy-4-pyrrolidinylquinazoline tagged with a 2-[18F]fluroethoxy group was developed in collaboration with our partner from the University of Leipzig (Institute of Pharmacy, compound [18F]IV).The nonradiactive compound IV has been synthesized as an inhibitor of phosphodiesterase 10A with moderate potency (PDE10A, KiPDE10A = 58 nM). It was also synthesized in radiolabelled form to yield a selective brain penetrable radiotracer [18F]IV.
Structure of the new 18F-labeled PDE10A-radiotracer and representative color-coded autoradiographic images of sagittal brain slices.
A) Distribution of radioactivity in vitro in rat brain after 60 min of incubation with 25 nM solution of [18F]IV, and B) 25 nM [18F]IV/ 1 μM MP-10, a highly specific ligand for PDE10A. C) Distribution of [18F]IV in mice brain ex vivo, obtained at 30 min p.i. of 100 MBq.
- Universität Leipzig, Leipzig, Germany
- Universitätsklinikum Leipzig, Leipzig, Germany
Biocrea GmbH, Radebeul, Germany
- Université Clermont Auvergne, France. Dr. Aurelie Maisonial-Besset, Dr. Emmanuel Moreau, Prof. Jean-Michel Chezal
- Liu, J.; Maisonial-Besset, A; Wenzel, B.; Canitrot, D.; Baufond, A.; Chezal, J.-M.; Brust, P.; Moreau, E.: "Synthesis and in vitro evaluation of new fluorinated quinoline derivatives with high affinity for PDE5: towards the development of new PET neuroimaging probes". Eur J Med Chem. 2017, in press
- Liu, J.; Wenzel, B.; Dukic-Stefanovic, S.; Teodoro, R.; Ludwig, F.-A.; Deuther-Conrad, W.; Schröder, S.; Chezal, J.-M.; Moreau, E.; Brust, P.; Maisonial-Besset, A.: "Development of a new radiofluorinated quinoline analog for PET imaging of phosphodiesterase 5 (PDE5) in brain"; Pharmaceuticals 2016, 9, 22; doi:10.3390/ph9020022.
Schröder, S.; Wenzel, B.; Deuther-Conrad, W.; Scheunemann, M.; Brust, P. "Novel radioligands for cyclic nucleotide phosphodiesterase imaging with positron emission tomography: An update on developments since 2012". Molecules. 2016, 21, 650.
Schröder, S.; Wenzel, B.; Deuther-Conrad, W.; Teodoro, R.; Egerland, U.; Kranz, M.; Schreunemann, M.; Höfgen, N.; Steinbach, J.; Brust, P.: "Synthesis, 18F-Radiolabelling and biological characterisation of novel fluoroalkylated triazine derivatives for in vivo imaging of phosphodiesterase 2A in brain via positron emission tomography". Molecules 2015, 20, 9591-9615.
- Schwan, G.; Barbar Asskar, G.; Höfgen, N.; Kubicova, L.; Funke, U.; Egerland, U.; Zahn, M.; Nieber, K.; Scheunemann, M.; Sträter, N.; Brust, P.; Briel, D. "Fluorine-containing 6,7-dialkoxybiaryl-based inhibitors for phosphodiesterase 10 A: synthesis and in vitro evaluation of inhibitory potency, selectivity, and metabolism". ChemMedChem. 2014, 9(7):1476-87.
- Funke, U.; Schwan, G.; Maionial, A.; Scheunemann, M.; Deuther-Conrad, W.; Fischer, S.; Hiller, A.; Sträter, N.; Nieber, K.; Briel, D.; Brust, P. "Radiosynthesis and Radiotracer Properties of a 7-(2-[18F]Fluoroethoxy)-6-methoxy-pyrrolidinylquinazoline for Imaging of PDE10A with PET". Pharmaceuticals. 2012, 5, 169-88.
- Nieber, K.; Erdmann, S.; Briel, D. et al. "Neue Halogenalkoxychinazoline, deren Herstellung und Verwendung," Patent Appl. 00401P0051DE, 2010
Financial Support by
- Deutsche Forschungsgemeinschaft - DFG
- European Regional Development Fund
- Federal Ministry of Education and Research (Procope)
- German Academic Exchange Service - DAAD together with the french Campus France within the PHC PROCOPE initiative