Microglia are the resident immune cells of the CNS and play an important role in the protection, homeostasis and surveillance of the brain parenchyma. Thus, a broad spectrum of functions and abilities can be attributed to them, like the constant scanning of the surrounding brain tissue, the secretion of inflammatory cytokines (e.g. interleukin 1 beta, interleukin 6, tumour necrosis factor α) or reactive oxygen species, the removal of cellular debris and de-and remyelination of neurons. This versatility is a result of the ability to switch between different phenotypes, each with its own cell morphology, gene expression and function. Thus, microglia can respond rapidly to injury or pathogens through a dynamic and reversible shift from homeostatic to activated microglia, which initiate an acute inflammatory reaction and subsequent neuroprotective care. Transcriptome analysis indicates that the ageing process affects the active interplay of damage and repair, resulting in a reduction of homeostatic microglia throughout the lifespan. In the onset and progression of neurodegenerative diseases, such as AD, this natural effect is drastically amplified, leading to a microglia polarization towards chronic activation and neuroinflammation. So far, it has proven challenging to obtain sufficient and satisfactory in vivo data which reflect the heterogeneous spectrum of microglia phenotypes and activation states. However, this real-time information would be necessary to develop new therapeutic approaches for neurodegenerative diseases, based on the manipulation of microglia polarization in order to prevent or reverse maladaptive activation. PET, a non-invasive and highly specific imaging method, represents a particularly suitable tool for imaging dynamic and complex processes in vivo, such as neuroinflammation. At present, PET is employed in clinical research to assess microglia activation. The most prevalent target to image activated microglia is the 18 kDa translocator protein (TSPO), although the biomarker is subject to several limitations. PET data interpretation is demanding since TSPO is expressed not only on microglia but also on endothelial cells and astrocytes. Furthermore, at elevated expression levels, it is not possible to distinguish between neuroprotective and neurotoxic phenotypes. Genetic polymorphism in humans can also result in low and high binding of PET tracers, creating a demand for more specific and universal imaging targets. Another example for a recent imaging target in neuroinflammatory diseases is the P2X7 receptor, given its close association with inflammatory processes and its significant role in the formation of inflammasomes. Nevertheless, it suffers from similar limitations such as multiple cell types expressing the target or a moderate level of expression in healthy subjects. While these two exemplary biomarkers and others are commonly used in research related to the activated phenotype, there are currently no PET tracers available for clinical use in imaging homeostatic microglia. In this context, the G-protein coupled purinergic 2Y type 12 receptor P2Y12R has emerged recently as a promising molecular target. In case of brain injury, P2Y12R detects extracellular nucleotides such as ADP and ATP, released from damaged neurons and glia cells and microglia activation is subsequently initiated. Receptor expression accompanies the morphological and functional changes from anti-inflammatory to pro-inflammatory states, with a distinct and rapid receptor down-regulation. This contrast emphasises P2Y12R as a promising surrogate for the dynamic and complex neuroinflammation process. The receptor has a clear functional involvement in microglia activation and is found specifically on microglia within the CNS. In the periphery, it is found on platelets, where it plays an essential role as ADP receptor in the signalling pathway to platelet aggregation. To date, several tracers targeting P2Y12R have been developed (Figure ). However, the reported compounds have only poor brain uptake and are therefore unsuitable for in vivo brain imaging. Van der Wildt and coworkers published two potent thienopyrimidine-based ligands, [ 11 C]1 and [ 18 F]2, which turned out to be substrates for efflux transporters, hindering their brain accumulation. Most recently, the same group published another highly affine P2Y12R PET tracer, based on a pyrazolidine-3,5-dione derivative. Unfortunately, this tracer demonstrated low in vivo stability and brain uptake. Other attempts focused on the development of small molecules based on the structure of the P2Y12R antagonist and platelet aggregation inhibitor AZD1283 5, but the compounds [ 11 C]4 and [ 11 C]5 were unable to cross the blood-brain barrier (BBB). Figure . Published P2Y12R radioligands. Nevertheless, the development process of AZD1283 5 has yielded interesting progenitor compounds, like compound 6, that promise better brain accessibility while retaining a moderate level of affinity for the target receptor (Figure ). On the basis of these structures, a set of 16 new compounds (7-22) was designed, synthesised and validated, aiming to provide a novel PET tracer candidate. The intent was to discover high affinity compounds while maintaining a sufficient brain permeability by varying substituents or linkers. Compound 12 was subsequently selected for further examination as a specific and brain-compatible PET tracer, due to its high target affinity and promising physiochemical properties. The compound was radiolabelled with fluorine-18 and tested in a set of in vitro and in vivo studies to confirm brain uptake and specificity. This work presents a further step towards P2Y12R imaging in the CNS by means of brain-permeable radiotracers, which could facilitate the characterisation of P2Y12R expression and activity in the context of neuroinflammation.