Visualizing GABA transporters in vivo: an overview of reported radioligands and future directions

Niels Knippenberg; Matthias Bauwens; Olaf Schijns; Govert Hoogland; Alexandru Florea; Kim Rijkers; Thomas J Cleij; Kasper Eersels; Bart van Grinsven; Hanne Diliën

doi:10.1186/s13550-023-00992-5

Visualizing GABA transporters in vivo: an overview of reported radioligands and future directions

EJNMMI Res. 2023 May 12;13(1):42. doi: 10.1186/s13550-023-00992-5.

Authors

Niels Knippenberg¹, Matthias Bauwens^{2

3}, Olaf Schijns^{4

5

6}, Govert Hoogland^{4

5}, Alexandru Florea^{2

3

7}, Kim Rijkers^{4

5

6}, Thomas J Cleij⁸, Kasper Eersels⁸, Bart van Grinsven⁸, Hanne Diliën⁸

Affiliations

¹ Sensor Engineering Department, Faculty of Science and Engineering, Maastricht University, 6200 MD, Maastricht, The Netherlands. niels.knippenberg@maastrichtuniversity.nl.
² Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074, Aachen, Germany.
³ Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre+ (MUMC+), 6229 HX, Maastricht, The Netherlands.
⁴ Department of Neurosurgery, Maastricht University Medical Centre+ (MUMC+), 6229 HX, Maastricht, The Netherlands.
⁵ School for Mental Health and Neuroscience (MHeNS), Maastricht University, 6200 MD, Maastricht, The Netherlands.
⁶ Academic Center for Epileptology (ACE), Maastricht University Medical Centre+ (MUMC+), 6229 HX, Maastricht, The Netherlands.
⁷ School for Cardiovascular Diseases (CARIM), Maastricht University Medical Centre+ (MUMC+), 6229 HX, Maastricht, The Netherlands.
⁸ Sensor Engineering Department, Faculty of Science and Engineering, Maastricht University, 6200 MD, Maastricht, The Netherlands.

Abstract

By clearing GABA from the synaptic cleft, GABA transporters (GATs) play an essential role in inhibitory neurotransmission. Consequently, in vivo visualization of GATs can be a valuable diagnostic tool and biomarker for various psychiatric and neurological disorders. Not surprisingly, in recent years several research attempts to develop a radioligand have been conducted, but so far none have led to suitable radioligands that allow imaging of GATs. Here, we provide an overview of the radioligands that were developed with a focus on GAT1, since this is the most abundant transporter and most of the research concerns this GAT subtype. Initially, we focus on the field of GAT1 inhibitors, after which we discuss the development of GAT1 radioligands based on these inhibitors. We hypothesize that the radioligands developed so far have been unsuccessful due to the zwitterionic nature of their nipecotic acid moiety. To overcome this problem, the use of non-classical GAT inhibitors as basis for GAT1 radioligands or the use of carboxylic acid bioisosteres may be considered. As the latter structural modification has already been used in the field of GAT1 inhibitors, this option seems particularly viable and could lead to the development of more successful GAT1 radioligands in the future.

Keywords: GABA; GABA transporter; GAT inhibitor; GAT radioligand; PET imaging.

Publication types

Review