Mapping dopamine with positron emission tomography: A note of caution

Please cite this article as: Dagher, A., Mappi 10.1016/j.neuroimage.2019.116203 Positron emission tomography (PET) imaging is uniquely suited to measuring neurotransmitter signaling in the human brain. PET tracers for neurotransmitter studies are ligands of the receptor or enzyme of interest labelled with positron emitting isotopes, usually 11C of 18F. By far the most frequent target of PET neurotransmitter imaging is dopamine, and the most commonly used tracer is [11C]raclopride, an antagonist of the dopamine D2 receptor (D2R), first developed by researchers at the Karolinska Institute (Farde et al., 1986). [11C]raclopride has also been used to map dopamine release in the living brain (Egerton et al., 2009). This is because binding depends on both the density of D2R (Bmax) and the tonic concentration of dopamine. Dopamine, unlike e.g. glutamate or GABA, is present outside neurons at constant levels. These so-called tonic levels of dopamine are maintained by constant low frequency firing of dopamine neurons and also by impulse-independent dopamine efflux (Sulzer et al., 2016). At baseline, the occupancy of D2R by dopamine is estimated at roughly 50–75% (Dreyer et al., 2010). The high affinity D2R is sensitive to these tonic concentrations, and therefore dopamine can exert bidirectional effects on D2R-bearing postsynaptic neurons. Both reductions and elevations in dopamine from its baseline are thought to convey information in the striatum, acting as signals for reinforcement learning (Cox et al., 2015; Frank and O’Reilly, 2006). It is because tonic occupancy is in the middle of the range that PET imaging with D2R ligands can be used to measure dopamine release, typically using a two-scan approach (baseline and “activation”). However, an inherent limitation in mapping D2R distribution or dopamine release with PET comes from the interaction of the properties that make a PET tracer suitable and the very large range of D2R densities across different brain areas. Indeed, there is a ten to one hundred-fold difference in the concentration of D2R between striatum and cortex (lower in cortex – see Fig. 1) (Hall et al., 1994). This is a problem because the affinity of a PET tracer needs to be optimum, that is neither too high nor too low. High affinity leads to slow equilibrium, while low affinity leads to low signal (Laruelle et al., 2003). A tracer whose affinity is optimum for the striatum will have too little binding in cortex to yield a