Molecular imaging of α7 nAChR in cancer and brain diseases: design and evaluation of novel 18F-labelled 1,4-diazabicyclo-[3.2.2]nonane based PET radiotracers
The ubiquitous expression and the particular intracellular signalling triggered by activation of the homomeric nicotinic acetylcholine receptor α7 nAChR in mammalian cells make this protein an interesting target for diagnostic and therapeutic approaches. α7 nAChR regulates not only the neurotransmitter release in brain regions related to learning, memory, and information processing but is also involved in cancer development and progression. Because density and functionality of α7 nAChR is closely connected with various neurological disorders and most types of cancer, non-invasive visualisation and quantification of α7 nAChR by positron emission tomography (PET) as well as receptor occupancy studies supporting novel pharmacological approaches has the potential to improve clinical diagnostics and drug development. The primary objective of this project is to design and evaluate 18F-labelled α7 nAChR PET radiotracers based on the 1,4-diazabicyclo-[3.2.2]nonane skeleton.
|Sagittal tomographic image of a porcine brain after injection of the radiotracer [18F]NS10743. The heterogeneous pattern of the intensity of radioactivity in the brain with a high accumulation in cortex (C) and thalamus (Th) and low accumulation in cerebellum (Cb) indicates specific binding of the radiotracer.|
- ABX GmbH, Radeberg, Germany
DanPET, Malmö, Sweden
- Neurosearch A/S, Ballerup, Denmark
- Universität Leipzig
- Universitätsklinikum Leipzig
- Yale University, New Haven, USA
- Hillmer A, Li S, Zheng M, Scheunemann M, Lin S, Nabulsi N, Holden D, Pracitto R, Labaree D, Ropchan J, Teodoro R, Deuther-Conrad W, Esterlis I, Cosgrove KP, Carson RE, Brust P, Huang Y. PET Imaging of α7 nicotinic acetylcholine receptors: A comparative study of [18F]ASEM and [18F]DBT-10 in non-human primates, and further evaluation of [18F]ASEM in humans. Eur J Nucl Med Molec Imaging. 2017, doi: 10.1007/s00259-017-3621-8.
- Hillmer A, Zheng M, Li S, Scheunemann M, Lin S, Holden D, Labaree D, Ropchan J, Deuther-Conrad W, Teodoro R, Carson R, Brust P, Huang Y. PET imaging evaluation of [18F]DBT-10, a novel radioligand specific to α7 nicotinic acetylcholine receptors, in nonhuman primates. Eur J Nucl Med Molec Imaging. 2016, 43:537-547.
- Rötering S., Scheunemann M, Günther R, Löser R, Hiller A, Peters D, Brust P, Fischer S, Steinbach J. Tos-Nos-Mos: Synthesis of different aryl sulfonate precursors for the radiosynthesis of the alpha7 nicotinic acetylcholine receptor radioligand [18F]NS14490. Appl Rad Isot. 2016, 114, 57-62.
- Teodoro R, Scheunemann M, Deuther-Conrad W, Wenzel B, Fasoli FM, Gotti C, Kranz M, Donat CK, Patt M, Hillmer A, Zheng M, Peters D, Steinbach J, Sabri O, Huang Y. Brust P. A promising PET tracer for imaging of α7 nicotinic acetylcholine receptors in the brain: Design, synthesis, and in vivo evaluation of a dibenzothiophene-based radioligand. Molecules. 2015, 20:18387-421.
- Teodoro R, Scheunemann M, Wenzel B, Kranz M, Patt M, Deuther-Conrad W, Steinbach J, Sabri O, Brust P. A high-yield automated radiosynthesisof the alpha-7 nicotinic receptor radioligand [18F]NS10743. Appl Rad Isot. 2014, 95, 76–84.
- Rötering S, Deuther-Conrad W, Cumming P, Donat CK, Scheunemann M, Fischer S, Xiong G, Steinbach J, Peters D, Sabri O, Bucerius J, Brust P. Imaging of α7 nicotinic acetylcholine receptors in brain and cerebral vasculature of juvenile pigs with [18F]NS14490. EJNMMI Research 2014, 4:43
- Rötering S, Scheunemann M, Fischer S, Hiller A, Peters D, Steinbach J, Deuther-Conrad W, Brust P Radiosynthesis and evaluation of [18F]NS14490 for molecular imaging of α7 nicotinic acetylcholine receptors. Bioorg Med Chem. 2013, 21, 2635–2642.
Brust P, Deuther-Conrad W. Development of radioligands for the imaging of α7 nicotinic acetylcholine receptors with positron emission tomography. Curr Drug Targets. 2012,13: 594-601.
Brust P, Deuther-Conrad W. Molecular imaging of α7 nicotinic acetylcholine receptors in vivo: current status and perspectives. Neuroimaging-Clinical Applications (ed. Peter Bright) 2012, ISBN 978-953-51-0200-71
Deuther-Conrad W, Fischer S, Hiller A, Becker G, Cumming P, Xiong G, Funke U, Sabri O, Peters D, Brust P. Assessment of α7 nicotinic acetylcholine receptor availability in juvenile pig brain with [18F]NS10743. Eur J Nucl Med Mol Imaging. 2011,38(8):1541-9.
Deuther-Conrad W, Fischer S, Hiller A, Nielsen EØ, Timmermann DB, Steinbach J, Sabri O, Peters D, Brust P. Molecular imaging of alpha7 nicotinic acetylcholine receptors: design and evaluation of the potent radioligand [18F]NS10743. Eur J Nucl Med Mol Imaging. 2009,36(5):791-800.
Financial support by
- Deutsche Forschungsgemeinschaft - DFG (DE 1165/2)