Contact

Porträt Prof. Dr. Brust, Peter; FWPN

Prof. Dr. Peter Brust
Head Neuroradiopharmaceuticals
p.brustAthzdr.de
Phone: +49 351 260 - 4610
Fax: +49 351 260 - 4699

Radioligands for PET Imaging of Phosphodiesterases 2A and 10A (PDE2A & PDE10A)

The enzymes PDE2A 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 and PDE10A are also involved in neuropathological and cancerous processes and therefore are interesting targets for molecular imaging approaches. Specific PET radioligands for PDE2A and PDE10A would allow the quantification of these enzymes in the human brain and in certain tumors.

 


  • PDE10A

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.

8F-labelled ligand for PDE10A.                       Autoradiographic images of sagittal brain slices with specific ligand for PDE10A.

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.

 

Partner

    • University of Leipzig, Institute of Pharmacy: Prof. Detlev Briel and co-workers, Prof. Karin Nieber and co- workers. University of Leipzig, Institute of Bioanalytical Chemistry : Prof. Norbert Sträter and co-workers.

    • Biocrea GmbH, Radebeul, Germany

Publications

    • K. Nieber, S. Erdmann, D. Briel et al. "Neue Halogenalkoxychinazoline, deren Herstellung und Verwendung," Patent Appl. 00401P0051DE, 2010.

    • 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.

    • 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.

  • PDE2A

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 and representative color-coded autoradiographic images of sagittal brain slices

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.

 

Partner

    • Biocrea GmbH, Radebeul, Germany

Publications

    • Stange, H.; Langen, B.; Egerland, U.; Hoefgen, N.; Priebs, M.; Malamas, M. S.; Erdei, J. J.; Ni, Y.: Triazine derivatives as inhibitors of phosphodiesterases, Patent WO 2010/054253 A1.
    • S. Schröder, B. Wenzel, W. Deuther-Conrad, R. Teodoro, U. Egerland, M. Kranz, M. Schreunemann, N. Höfgen, J. Steinbach, P. Brust:
      "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 20 (2015) 9591-9615.
    • S. Schröder, B. Wenzel, W. Deuther-Conrad, M. Scheunemann, P. Brust:

      „Novel radioligands for cyclic nucleotide phosphodiesterase imaging with positron emission tomography: an update on developments since 2012“

      Molecules (2016) 21, 650.


Contact

Prof. Dr. Peter Brust
Head Neuroradiopharmaceuticals
p.brustAthzdr.de
Phone: +49 351 260 - 4610
Fax: +49 351 260 - 4699