Recent advances in PET measures of brain 5-HT release

Area of Science:

• Neuroscience
• Psychiatry
• Radiochemistry

Background:

• Serotonin (5-hydroxytryptamine, 5-HT) is a key neuromodulator involved in numerous psychological and physiological functions.
• Dysregulation of the serotonergic system is implicated in various psychiatric disorders, highlighting the need for in vivo measurement of 5-HT dynamics.
• Previous limitations in tracer sensitivity and pharmacological challenge potency hindered accurate assessment of endogenous 5-HT release.

Purpose of the Study:

• To review advancements in non-invasive measurement of endogenous 5-HT release in the living human brain.
• To highlight novel tracers and optimized challenge paradigms for quantifying 5-HT dynamics in vivo.
• To discuss the shift in research focus from feasibility to optimal strategies for measuring serotonergic system activity.

Main Methods:

• Utilizing Positron Emission Tomography (PET) neuroimaging combined with pharmacological challenges to stimulate 5-HT release.
• Employing novel agonist radioligands (e.g., [11C]AZ10419369, [11C]Cimbi-36) and antagonist tracers (e.g., [18F]Altanserin).
• Refining challenge designs with pharmacological 5-HT releasers (e.g., fenfluramine, amphetamine) and integrating hybrid PET/MR imaging.

Main Results:

• Novel tracers and optimized challenge paradigms demonstrate sensitivity to changes in endogenous 5-HT.
• Reproducible detection of acute 5-HT release is now achievable in both preclinical and human studies.
• Advances enable the assessment of neurovascular aspects through hybrid PET/MR imaging.

Conclusions:

• Significant progress has been made in measuring serotonergic dynamics in vivo.
• Current methodologies allow for sensitive and reproducible quantification of 5-HT release.
• The field has moved towards optimizing strategies for studying the serotonergic system in health and disease.