Measuring serotonin synthesis: from conventional methods to PET tracers and their (pre)clinical implications

Abstract

The serotonergic system of the brain is complex, with an extensive innervation pattern covering all brain regions and endowed with at least 15 different receptors (each with their particular distribution patterns), specific reuptake mechanisms and synthetic processes. Many aspects of the functioning of the serotonergic system are still unclear, partially because of the difficulty of measuring physiological processes in the living brain. In this review we give an overview of the conventional methods of measuring serotonin synthesis and methods using positron emission tomography (PET) tracers, more specifically with respect to serotonergic function in affective disorders. Conventional methods are invasive and do not directly measure synthesis rates. Although they may give insight into turnover rates, a more direct measurement may be preferred. PET is a noninvasive technique which can trace metabolic processes, like serotonin synthesis. Tracers developed for this purpose are α-[11C]methyltryptophan ([11C]AMT) and 5-hydroxy-L-[β-11C]tryptophan ([11C]5-HTP). Both tracers have advantages and disadvantages. [11C]AMT can enter the kynurenine pathway under inflammatory conditions (and thus provide a false signal), but this tracer has been used in many studies leading to novel insights regarding antidepressant action. [11C]5-HTP is difficult to produce, but trapping of this compound may better represent serotonin synthesis. AMT and 5-HTP kinetics are differently affected by tryptophan depletion and changes of mood. This may indicate that both tracers are associated with different enzymatic processes. In conclusion, PET with radiolabelled substrates for the serotonergic pathway is the only direct way to detect changes of serotonin synthesis in the living brain.

Serotonin Metabolites in the Cerebrospinal Fluid in Sudden Infant Death Syndrome

“…In addition, 5-HIAA in the brain extracellular space diffuses into the CSF, such that this compartment serves as a so-called 5-HIAA “sink” (50). Serotonin itself cannot reliably be measured in the CSF because its levels are constitutively negligible (less than 10 pg/ml) (51). Nevertheless, the CSF concentration of 5-HIAA correlates with 5-HT levels and turnover in brain parenchyma (29, 52).…”

Serotonin and molecular neuroimaging in humans using PET

“…Another ligand, used to trap TPH is the carbon-labeled [ 11 C]5-hydroxytryptophan ([ 11 C]5-HTP). It is proposed to be more suitable to actually measure 5-HT synthesis, but is still less widely used due to its complicated radiosynthesis (for review, see Visser et al 2011).…”

Assessment of Peripheral Serotonin Synthesis Using Stable Isotope‐Labeled Tryptophan

“…15,17 The positron emission tomography (PET) tracers a-[ 11 C]methyltryptophan ([ 11 C]AMT) and 5-hydroxy-L-[b-11 C]tryptophan ([ 11 C]5-HTP) have been utilized clinically as surrogates of 5-HT synthesis. 18 However, PET only follows the radioactivity, and the widely used [ 11 C]AMT PET may mainly reflect the metabolically dominant kynurenine pathway (90% of Trp metabolism) and/ or Trp uptake. [18][19][20] Although [ 11 C]5-HTP is a useful tool for staging neuroendocrine tumors, 21 it is complex to produce and does not probe the rate-limiting TPH step.…”

“…18 However, PET only follows the radioactivity, and the widely used [ 11 C]AMT PET may mainly reflect the metabolically dominant kynurenine pathway (90% of Trp metabolism) and/ or Trp uptake. [18][19][20] Although [ 11 C]5-HTP is a useful tool for staging neuroendocrine tumors, 21 it is complex to produce and does not probe the rate-limiting TPH step. Development of new methods to measure 5-HT synthesis is timely due to renewed interest in TPH inhibitors consecutive to telotristat ethyl's approval and limitations of existing methodology.…”

“…Inconvenient 24‐hour urine collection and measurement of the 5‐HT metabolite 5‐HIAA is frequently used as a diagnostic for carcinoid syndrome and was also used as a biomarker of TPH inhibition in the telotristat ethyl pivotal study . The positron emission tomography (PET) tracers α‐[ 11 C]methyltryptophan ([ 11 C]AMT) and 5‐hydroxy‐L‐[β‐ 11 C]tryptophan ([ 11 C]5‐HTP) have been utilized clinically as surrogates of 5‐HT synthesis . However, PET only follows the radioactivity, and the widely used [ 11 C]AMT PET may mainly reflect the metabolically dominant kynurenine pathway (∼90% of Trp metabolism) and/or Trp uptake .…”