**Guillaume Becker \*,**†**, Sylvestre Dammicco** †**, Mohamed Ali Bahri** † **and Eric Salmon** †

GIGA-Cyclotron Research Center-in vivo imaging, University of Liège, Allée du 6 Août, B30,

4000 Liege, Belgium; sdammicco@uliege.be (S.D.); m.bahri@uliege.be (M.A.B.); eric.salmon@uliege.be (E.S.)

**\*** Correspondence: g.becker@uliege.be; Tel.: +32-4366-2334

† These authors have equally contributed.

Academic Editors: Anne Roivainen and Xiang-Guo Li Received: 24 April 2020; Accepted: 8 May 2020; Published: 14 May 2020

**Abstract:** Many neurological disorders are related to synaptic loss or pathologies. Before the boom of positrons emission tomography (PET) imaging of synapses, synaptic quantification could only be achieved in vitro on brain samples after autopsy or surgical resections. Until the mid-2010s, electron microscopy and immunohistochemical labelling of synaptic proteins were the gold-standard methods for such analyses. Over the last decade, several PET radiotracers for the synaptic vesicle 2A protein have been developed to achieve in vivo synapses visualization and quantification. Different strategies were used, namely radiolabelling with either 11C or 18F, preclinical development in rodent and non-human primates, and binding quantification with different kinetic modelling methods. This review provides an overview of these PET tracers and underlines their perspectives and limitations by focusing on radiochemical aspects, as well as preclinical proof-of-concept and the main clinical outcomes described so far.

**Keywords:** SV2A protein; PET radiotracers; synaptic loss; radiochemistry; preclinical development; clinical outcomes
