Radioligands for Tropomyosin Receptor Kinase (Trk) Positron Emission Tomography Imaging

Pharmaceuticals (Basel). 2019 Jan 3;12(1):7. doi: 10.3390/ph12010007.

Ralf Schirrmacher ¹, Justin J Bailey ², Andrew V Mossine ³, Peter J H Scott ⁴ ⁵, Lena Kaiser ⁶, Peter Bartenstein ⁷, Simon Lindner ⁸, David R Kaplan ⁹, Alexey Kostikov ¹⁰, Gert Fricker ¹¹, Anne Mahringer ¹², Pedro Rosa-Neto ¹³, Esther Schirrmacher ¹⁴, Carmen Wängler ¹⁵, Björn Wängler ¹⁶, Alexander Thiel ¹⁷ ¹⁸, Jean-Paul Soucy ¹⁹, Vadim Bernard-Gauthier ²⁰ ²¹

Affiliations

1 Department of Oncology, Division of Oncological Imaging, University of Alberta, Edmonton, Alberta T6G 2R3, Canada. schirrma@ualberta.ca.
2 Department of Oncology, Division of Oncological Imaging, University of Alberta, Edmonton, Alberta T6G 2R3, Canada. jjbailey@ualberta.ca.
3 Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, MI, 48109, USA. amossine@med.umich.edu.
4 Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, MI, 48109, USA. pjhscott@med.umich.edu.
5 The Interdepartmental Program in Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. pjhscott@med.umich.edu.
6 Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, Munich 81377, Germany. Lena.Kaiser@med.uni-muenchen.de.
7 Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, Munich 81377, Germany. Peter.Bartenstein@med.uni-muenchen.de.
8 Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, Munich 81377, Germany. Simon.Lindner@med.uni-muenchen.de.
9 Program in Neurosciences and Mental Health, Hospital for Sick Children and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5G 0A4. dkaplan@sickkids.ca.
10 McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada. alexey.kostikov@mcgill.ca.
11 Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg 69120, Germany. gert.fricker@uni-hd.de.
12 Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg 69120, Germany. mahringer@uni-hd.de.
13 Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, Douglas Mental Health University Institute, Montreal, QC H4H 1R3, Canada. pedro.rosa.neto@gmail.com.
14 Department of Oncology, Division of Oncological Imaging, University of Alberta, Edmonton, Alberta T6G 2R3, Canada. eschirrm@ualberta.ca.
15 Biomedical Chemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany. Carmen.Waengler@medma.uni-heidelberg.de.
16 Molecular Imaging and Radiochemistry, Department of Clinical Radiology and Nuclear Medicine, Medical Faculty Mannheim of Heidelberg University, Theodor-Kutzer-Ufer 1-3, Mannheim 68167, Germany. Bjoern.Waengler@medma.uni-heidelberg.de.
17 McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada. alexander.thiel@mcgill.ca.
18 Jewish General Hospital, Lady Davis Institute, Montreal, QC HT3 1E2, Canada. alexander.thiel@mcgill.ca.
19 McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A 2B4, Canada. jean-paul.soucy@mcgill.ca.
20 Azrieli Centre for Neuro-Radiochemistry, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON M5T 1L8, Canada. Vadim.bernard-gauthier@camhpet.ca.
21 Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada. Vadim.bernard-gauthier@camhpet.ca.

PMID: 30609832 DOI: 10.3390/ph12010007

Abstract

The tropomyosin receptor kinases family (TrkA, TrkB, and TrkC) supports neuronal growth, survival, and differentiation during development, adult life, and aging. TrkA/B/C downregulation is a prominent hallmark of various neurological disorders including Alzheimer's disease (AD). Abnormally expressed or overexpressed full-length or oncogenic fusion TrkA/B/C proteins were shown to drive tumorigenesis in a variety of neurogenic and non-neurogenic human cancers and are currently the focus of intensive clinical research. Neurologic and oncologic studies of the spatiotemporal alterations in TrkA/B/C expression and density and the determination of target engagement of emerging antineoplastic clinical inhibitors in normal and diseased tissue are crucially needed but have remained largely unexplored due to the lack of suitable non-invasive probes. Here, we review the recent development of carbon-11- and fluorine-18-labeled positron emission tomography (PET) radioligands based on specifically designed small molecule kinase catalytic domain-binding inhibitors of TrkA/B/C. Basic developments in medicinal chemistry, radiolabeling and translational PET imaging in multiple species including humans are highlighted.

Keywords

neurodegeneration; oncogenic fusions; positron emission tomography; tropomyosin receptor kinase.

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