Application of cross-species PET imaging to assess neurotransmitter release in brain

Abstract

RationaleThis review attempts to summarize the current status in relation to the use of positron emission tomography (PET) imaging in the assessment of synaptic concentrations of endogenous mediators in the living brain.ObjectivesAlthough PET radioligands are now available for more than 40 CNS targets, at the initiation of the Innovative Medicines Initiative (IMI) “Novel Methods leading to New Medications in Depression and Schizophrenia” (NEWMEDS) in 2009, PET radioligands sensitive to an endogenous neurotransmitter were only validated for dopamine. NEWMEDS work-package 5, “Cross-species and neurochemical imaging (PET) methods for drug discovery”, commenced with a focus on developing methods enabling assessment of changes in extracellular concentrations of serotonin and noradrenaline in the brain.ResultsSharing the workload across institutions, we utilized in vitro techniques with cells and tissues, in vivo receptor binding and microdialysis techniques in rodents, and in vivo PET imaging in non-human primates and humans. Here, we discuss these efforts and review other recently published reports on the use of radioligands to assess changes in endogenous levels of dopamine, serotonin, noradrenaline, γ-aminobutyric acid, glutamate, acetylcholine, and opioid peptides. The emphasis is on assessment of the availability of appropriate translational tools (PET radioligands, pharmacological challenge agents) and on studies in non-human primates and human subjects, as well as current challenges and future directions.ConclusionsPET imaging directed at investigating changes in endogenous neurochemicals, including the work done in NEWMEDS, have highlighted an opportunity to further extend the capability and application of this technology in drug development.

News and views on in-vivo imaging of neurotransmission using PET and MRI

“…These studies showed reduced cortical radioligand binding, albeit to a lesser extent than striatal [ 11 C]raclopride displacement, that indicated that these radiotracers may allow for monitoring of changes in cortical synaptic dopamine concentrations when endogenous dopamine was available for release, also in clinical experiments 4 . The changes in radiotracer binding were proportional to changes in dopamine concentrations as measured in microdialysis experiments; findings that reflect modulation of dopamine release into the synaptic gap instead of inherently reflecting changes in the extracellular fluid dopamine concentration across drugs with different modes of action 2 .…”

“…To date, the main class of radiotracers shown to be sensitive for endogenous neurotransmitter release is specific to the dopamine receptor system (for an overview see for example Finnema et al 2015 2 ). Current research indicates that novel radiotracers developed for the serotonin (5-hydroxytryptamine, 5-HT), the opioid and the cholinergic system are also sensitive for changes in extracellular concentrations of their respective neurotransmitters.…”

“…This might be due to the fact that dopamine has significantly lower affinity to the D1 receptor, which predominantly exist in the low-affinity state, than D2 receptor in the striatum 10,11 . Important to note here is that the changes in the binding potential are typically interpreted according to a competition model, e.g., reflecting a change in dissociation rate constant K D , but several observations suggest a contribution of dopamine receptor internalization as well 2 .…”

“…Interventions to either elevate or deplete extracellular serotonin, however, did not affect [ 11 C]DASB binding in humans 16 . Increases in synaptic serotonin concentration have also not or not consistently been shown to influence binding of the high-affinity 5-HT 1A receptor ligand [ 11 C]WAY100635, or other 5-HT 1A receptor antagonistic tracers such as [ 18 F]MPPF, [ 18 F]FPWAY or [ 11 C]CUMI-101, possibly due to the effects of 5-HT 1A autoreceptor activation 2 . Antagonist radiotracers such as [ 18 F]setoperone, [ 18 F]altanserin, and [ 11 C]MDL 100907 for 5-HT 2A receptor have generally not shown sensitivity to endogeneous serotonin release in PET studies.…”

“…[ 11 C]AF150(S), which is an M1-selective mACh receptor agonist radiotracer also revealed preliminary hints for sensitivity to assess changes in extracellular acetylcholine concentrations 26 but this has not been further evaluated, or translated to humans so far. Other radiotracers that are subtype non-selective, such as 11 C-labelled (+)3-MPB, (+)3-EPB, (+)3-PPB, and NMPYB have been tested showing either no ((+)3-MPB, NMPYB) or significant changes ((+)3-EPB, (+)3-PPB) after increases in endogenous acetylcholine levels 2 .…”