Molecular imaging of α7 nAChR in cancer and brain diseases
With this project we seek to develop a tool for non-invasive quantification of the α7 subtype of nicotinic acetylcholine receptors (α7 nAChR) expressed in brain to better understand the involvement of this ligand-gated Ca2+ channel in the biology of brain cancers. Based on ex vivo data, a close connection between changes in the density and functionality of α7 nAChR with various neurological disorders and most types of cancer has been assumed. But the visualization of these alterations in vivo by clinically relevant imaging technologies such as PET is still challenging due to limitations in receptor-binding radiotracers.
Accordingly, we are working on the design, synthesis, radiolabeling, and preclinical evaluation of 18F-labelled α7 nAChR PET radiotracers. In the past years, we have learned a great deal on the suitability of small molecules substituted with a 1,4-diazabicyclo-[3.2.2]nonane, such as [18F]DBT-10 or [18F]NS10743, for detection of α7 nAChR expressed in brain of different species.
Scheme of the radiosynthesis of the α7 nAChR-binding radiotracer [18F]DBT10 (Ki α7 nAChR = 0.6 nM) and uptake of [18F]DBT-10 in the brain of a rhesus monkey ( [18F]DBT-10 VT/fP and corresponding MR images).
Using this expertise from earlier studies in medicinal chemistry, radiochemistry, and preclinical evaluation, work aims now to characterize the expression pattern of α7 nAChR in glioblastoma.
To achieve this objective, we establish orthotopic tumor models in mouse and study the suitability of established and new radiotracers for the analysis of spatial and temporal changes of the expression of α7 nAChR by small animal PET/MRI studies.
|Small animal PET/MR image of the tumoral [18F]NS10743 uptake in a U87-MG glioblastoma xenograft mouse.|
- ABX GmbH, Radeberg, Germany
DanPET, Malmö, Sweden
- Maastricht University Medical Center, Maastricht, Netherlands
- Mahidol University, Bangkok, Thailand
- National Cyclotron and PET Centre, Bangkok, Thailand
- National Institute of Radiological Sciences, Inage-ku, Chiba, Japan
- Neurosearch A/S, Hallerup, Denmark
- Universität Leipzig, Leipzig, Germany
- Universitätsklinikum Leipzig, Leipzig, Germany
- Yale University, New Haven, USA
DFG DE 1165/2-1, DFG DE 1165/2-3
Molecular insights into stereoselective binding of quinuclidine-triazole derivatives to α7 and α3β4 nicotinic acetylcholine receptors
Arunrungvichian K, Sarasamkan J, Schüürmann G, Brust P, Vajragupta O (2018)
Synthesis and radiofluorination of novel fluoren-9-one based derivatives for the imaging of α7 nicotinic acetylcholine receptor with PETTeodoro R, Scheunemann M, Wenzel B, Peters D, Deuther-Conrad W, Brust P. Bioorganic and Medicinal Chemistry Letters, Volume 28, Issue 9, 15 May 2018 May 15;28(9):1471-1475.
- Radiosynthesis of (S)-[18F]T1: The first PET radioligand for molecular imaging of α3β4 nicotinic acetylcholine receptors
Sarasamkan J, Fischer S, Deuther-Conrad W, Ludwig FA, Scheunemann M, Arunrungvichian K, Vajragupta O, Brust P. Applied Radiation and Isotopes, Volume 124, June 2017, Pages 106-113
- PET imaging of α7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans
Hillmer AT, Li S, Zheng MQ, Scheunemann M, Lin SF, Nabulsi N, Holden D, Pracitto R, Labaree D, Ropchan J, Teodoro R, Deuther-Conrad W, Esterlis I, Cosgrove KP, Brust P, Carson RE, Huang Y. European Journal of Nuclear Medicine and Molecular Imaging, Volume 44, Issue 6, 1 June 2017, Pages 1042-1050
PET imaging of α7 nicotinic acetylcholine receptors in a heterotopic xenograft model of brain cancer
Deuther-Conrad W, Neuber C, Teodoro R, Kranz M, Belter B, Peters D, Pietzsch J, Brust P. Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 60 Issue S1 Supplement: The 22nd International Symposium on Radiopharmaceutical Sciences (ISRS 2017), Dresden, Germany, May 14-19, 2017
Varying chirality across nicotinic acetylcholine receptor subtypes–stereoselective binding of quinuclidine triazole derivatives
Sarasamkan J, Scheunemann M, Apaijai N, Palee S, Parichatikanond W, Arunrungvichian K, Fischer S, Chattipakorn S, Deuther-Conrad W, Schüürmann G, Brust P, Vajragupta O. ACS Medicinal Chemistry Letters, Volume 7, Issue 10, August 2016, Pages 890-895
PET imaging evaluation of [18F]DBT-10, a novel radioligand specific to α7 nicotinic acetylcholine receptors, in nonhuman primates
Hillmer AT, Zheng MQ, Li S, Scheunemann M, Lin SF, Holden D, Labaree D, Ropchan J, Teodoro R, Deuther-Conrad W, Carson RE, Brust P, Huang Y. European Journal of Nuclear Medicine and Molecular Imaging, Volume 43, Issue 3, 1 March 2016, Pages 537-547
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
Teodoro R, Scheunemann M, Deuther-Conrad W, Wenzel B, Fasoli FM, Gotti C, Kranz M, Donat CK, Patt M, Hillmer A, Zheng MQ, Peters D, Steinbach J, Sabri O, Huang Y, Brust P. Molecules, Volume 20, Issue 10, 9 October 2015, Pages 18387-18421
A high-yield automated radiosynthesis of the alpha-7 nicotinic receptor radioligand [18F]NS10743
Teodoro R, Wenzel B, Oh-Nishi A, Fischer S, Peters D, Suhara T, Deuther-Conrad W, Brust P. Applied Radiation and Isotopes, Volume 95, January 01, 2015, Pages 76-84
Imaging of α7 nicotinic acetylcholine receptors in brain and cerebral vasculature of juvenile pigs with [18F]NS14490
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. EJNMMI Research, Volume 4, Issue 1, 1 December 2014, Article number 43, Pages 1-11
Radiosynthesis and first evaluation in mice of [18F]NS14490 for molecular imaging of α7 nicotinic acetylcholine receptors
Rötering S, Scheunemann M, Fischer S, Hiller A, Peters D, Deuther-Conrad W, Brust P. Bioorganic and Medicinal Chemistry, Volume 21, Issue 9, 1 May 2013, Pages 2635-2642
Development of radioligands for the imaging of α7 nicotinic acetylcholine receptors with positron emission tomography
Brust P, Peters D, Deuther-Conrad W. Current Drug Targets, Volume 13, Issue 5, May 2012, Pages 594-601
Assessment of a7 nicotinic acetylcholine receptor availability in juvenile pig brain with [18F]NS10743
Deuther-Conrad W, Fischer S, Hiller A, Becker G, Cumming P, Xiong G, Funke U, Sabri O, Peters D, Brust P. European Journal of Nuclear Medicine and Molecular Imaging, Volume 38, Issue 8, August 2011, Pages 1541-1549
Molecular imaging of α7 nicotinic acetylcholine receptors: Design and evaluation of the potent radioligand [18F]NS10743
Deuther-Conrad W, Fischer S, Hiller A, Stergaard Nielsen E, Brunicardi Timmermann D, Steinbach J, Sabri O, Peters D, Brust P. European Journal of Nuclear Medicine and Molecular Imaging, Volume 36, Issue 5, May 2009, Pages 791-800