Kinetic Compartment Modeling of [¹¹C]-5-Hydroxy-L-Tryptophan for Positron Emission Tomography Assessment of Serotonin Synthesis in Human Brain

Abstract

Summary:The substrate for the second enzymatic step in serotonin synthesis, 5-hydroxy-L-tryptophan, labeled in the ␤-position ([ 11 C]-HTP), was used for positron emission tomography (PET) measurements in six healthy human participants, examined on two occasions. One-and two-tissue kinetic compartment modeling of time-radioactivity curves was performed, using arterial, metabolite-corrected [11 C]-HTP values as input function. The availability of unchanged tracer in arterial blood plasma was Ն 80% up to 60 minutes after injection, while [ 11 C]-hydroxyindole acetic acid and [ 11 C]-serotonin accounted for the remaining radioactivity, amounting to Յ16% and Յ4%, respectively. Compartment modeling was performed for brain stem, putamen, caudate nucleus, anterior cingulate, white matter, and superior occipital, occipitotemporal, and temporal cortices. The average biologic half-life for plasma-to-tissue equilibrium was 7 to 12 minutes, and the volume of distribution was 0.2 to 0.5 L·mL

5‐HT radioligands for human brain imaging with PET and SPECT

“…[ 11 C]AMT and [ 11 C]HTP binding were found to correlate in some postmortem studies, but not in a head‐tohead comparison study in rhesus monkeys . More in vivo validation studies are required if firm conclusions are to be drawn about the suitability of these tracers for estimating 5‐HT synthesis.…”

“…In humans, [ 11 C]HTP utilization rates were shown to be region‐dependent and could be altered by serotonergic pharmacological challenges, suggesting that data from PET studies using [ 11 C]HTP might be interpreted as a measure of brain 5‐HT turnover. A later study showed that human PET data from this tracer could be reliably modelled when using a model that included irreversible trapping of the tracer . As for [ 11 C]AMT, the majority of studies using [ 11 C]HTP are in diagnostic investigations in pathological conditions rather than investigating 5‐HT synthesis per se.…”

Functional neuroimaging of genetic variation in serotonergic neurotransmission

“…The application of additional functional neuroimaging modalities, most notably radioligand‐specific positron emission tomography (PET), may provide a powerful tool for elucidating these pathways. For example, radioligands of increasing specificity and flexibility have been developed to probe both 5‐HT synthesis (Hagberg et al . 2002) and 5‐HTT availability (Meyer et al .…”

Role of positron emission tomography imaging in Multiple Endocrine Neoplasia syndromes

“…demonstrated a lower sensitivity of 73% but a high specificity of 100% for 11 C‐HED PET in detecting MEN‐2‐related pheochromocytomas compared to sporadic pheochromocytomas(Yamamoto et al ., ). On the other hand, 11 C‐HTP imaging depends on the tissue availability of the serotonin precursor tryptophan and highly correlates with the tissue serotonin concentration (Hagberg et al ., ).…”

“…Yamamoto et al demonstrated a lower sensitivity of 73% but a high specificity of 100% for 11 C-HED PET in detecting MEN-2-related pheochromocytomas compared to sporadic pheochromocytomas (Yamamoto et al, 2012). On the other hand, 11 C-HTP imaging depends on the tissue availability of the serotonin precursor tryptophan and highly correlates with the tissue serotonin concentration (Hagberg et al, 2002). A recent prospective study by van Asselt et al, (2015) evaluating 41 patients with MEN-1 syndrome reported that the diagnostic performance of 11 C-HTP PET in detecting pancreatic NETs is similar to that of CT/MRI plus somatostatin receptor scintigraphy and better compared with somatostatin receptor scintigraphy alone.…”