Molecular imaging of the adenosine receptors A_2A and A_2B in cancer

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Adenosine receptor (AR) agonists and antagonists have been developed for various therapeutic applications, including the treatment of cancer. However, the potential of ARs as new prognostic and diagnostic tumour markers has not yet been fully explored. In particular, a non-invasive assessment of the status of the two AR subtypes A_2A and A_2B in brain tumours is still lacking. Positron emission tomography (PET), which uses radioactive probes (PET radiotracers) to visualise and quantify such tumour markers, is a non-invasive, sensitive and highly specific imaging method. In the context of neurodegenerative diseases, our group has developed the two PET radiotracers [¹⁸F]FLUDA and [¹⁸F]PYM81 for imaging of the AR subtypes A_2A and A_2B, resp. Now we are aiming to investigate their suitability for PET imaging of these receptor subtypes in brain tumours and to develop further suitable radiotracers through optimisation of the lead structures by our medicinal chemistry and radiochemistry experts. Appropriate PET radiotracers for the non-invasive quantification of adenosine receptor availability would provide clinicians a tool for further characterisation of brain cancer, leading to more effective and personalised patient treatment.

The biological evaluation is carried out at different levels. In addition to binding studies on human brain tumour samples, various other in vitro approaches (cell uptake studies, autoradiographies) as well as in vivo studies using preclinical models (rodents, CAM tumour models) are used to investigate the binding profile and pharmacokinetics of the radiotracers.

 

Partners

• Universitätsklinik und Poliklinik für Neurochirurgie des Universitätsklinikums Halle (Dr. Maximilian Scheer)

• Pharma Center Bonn, University of Bonn (Prof. Christa E. Müller, Dr. Sonja Hinz)

• Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden (Prof. Richard H.W. Funk, Prof. Heinz Reichmann, Dr. Francisco Pan-Montojo)

• ROTOP Pharmaka GmbH, Dresden (Jens Junker, Dr. Thu Hang Lai)

• Friedrich Schiller University Jena (Prof. Carsten Hoffmann)

Financial support

• BMBF (German Federal Ministry for Education and Research) within the BioPharma initiative “Neuroallianz”

• EFRE (European Regional Development Fund) together with the Free State of Saxony

Publications

• Lai, T. H.; Wenzel, B.; Moldovan, R.-P.; Brust, P.; Kopka, K.; Teodoro, R.
  Automated radiosynthesis of the adenosine A_2A receptor-targeting radiotracer [¹⁸F]FLUDA
  J. Label. Compd. Radiopharm. 65 (2022), 162-166; DOI: 10.1002/jlcr.3970

• Gündel, D.; Toussaint, M.; Lai, T. H.; Deuther-Conrad, W.; Cumming, P.; Schröder, S.; Teodoro, R.; Moldovan, R.-P.; Pan-Montojo, F.; Sattler, B.
  Quantitation of the A_2A adenosine receptor density in the striatum of mice and pigs with [¹⁸F]FLUDA by positron emission tomography
  Pharmaceuticals 15 (2022), 516; DOI: 10.3390/ph15050516

• Gündel, D.; Lai, T. H.; Dukic-Stefanovic, S.; Teodoro, R.; Deuther-Conrad, W.; Toussaint, M.; Moldovan, R.-P.; Kopka, K.; Boknik, P.; Hofmann, B.; Gergs, U.; Neumann, J.; Brust, P.
  Non-invasive assessment of locally overexpressed human adenosine 2A receptors in the heart of transgenic mice
  Int. J. Mol. Sci. 23 (2022), 1025; DOI: 10.3390/ijms23031025

• Lindemann, M.; Dukic-Stefanovic, S.; Hinz, S.; Deuther-Conrad, W.; Teodoro, R.; Juhl, C.; Steinbach, J.; Brust, P.; Müller, C. E.; Wenzel, B.
  Synthesis of novel fluorinated xanthine derivatives with high adenosine A_2B receptor binding affinity
  Pharmaceuticals 14 (2021), 485; DOI: 10.3390/ph14050485

• Lai, T. H.; Toussaint, M.; Teodoro, R.; Dukic-Stefanovic, S.; Gündel, D.; Ludwig, F.-A.; Wenzel, B.; Schröder, S.; Sattler, B.; Moldovan, R.-P.; Falkenburger, B. H.; Sabri, O.; Deuther-Conrad, W.; Brust, P.
  Improved in vivo PET imaging of the adenosine A_2A receptor in the brain using [¹⁸F]FLUDA, a deuterated radiotracer with high metabolic stability
  Eur. J. Nucl. Med. Mol. Imaging 48 (2021), 2727-2736; DOI: 10.1007/s00259-020-05164-4

• Lindemann, M.; Moldovan, R.-P.; Hinz, S.; Deuther-Conrad, W.; Gündel, D.; Dukic-Stefanovic, S.; Toussaint, M.; Teodoro, R.; Juhl, C.; Steinbach, J.; Brust, P.; Müller, C. E.; Wenzel, B.
  Development of a radiofluorinated adenosine A_2B receptor antagonist as potential ligand for PET imaging
  Int. J. Mol. Sci. 21 (2020), 3197; DOI: 10.3390/ijms21093197

• Schröder, S.; Lai, T. H.; Toussaint, M.; Kranz, M.; Chovsepian, A.; Shang, Q.; Dukic-Stefanovic, S.; Deuther-Conrad, W.; Teodoro, R.; Wenzel, B.; Moldovan, R.-P.; Pan-Montojo, F.; Brust, P.
  PET Imaging of the Adenosine A_2A Receptor in the Rotenone-Based Mouse Model of Parkinson’s Disease with [¹⁸F]FESCH Synthesized by a Simplified Two-Step One-Pot Radiolabeling Strategy
  Molecules 25 (2020) 7, 1633; DOI: 10.3390/molecules25071633

• Lindemann, M.; Hinz, S.; Deuther-Conrad, W.; Namasivayam, V.; Dukic-Stefanovic, S.; Teodoro, R.; Toussaint, M.; Kranz, M.; Juhl, C.; Steinbach, J.; Brust, P.; Müller, C. E.; Wenzel, B.
  Radiosynthesis and in vivo evaluation of a fluorine-18 labeled pyrazine based radioligand for PET imaging of the adenosine A_2B receptor
  Bioorg. Med. Chem. 26 (2018), 4650-4663; DOI: 10.1016/j.bmc.2018.07.045