[¹¹C]5-HTP and microPET are Not Suitable for Pharmacodynamic Studies in the Rodent Brain

Abstract

The PET tracer [(11)C]5-hydroxytryptophan ([(11)C]5-HTP), which is converted to [(11)C]5-hydroxytryptamine ([(11)C]5-HT) by aromatic amino acid decarboxylase (AADC), is thought to measure 5-HT synthesis rates. But can we measure these synthesis rates by kinetic modeling of [(11)C]5-HTP in rat? Male rats were scanned with [(11)C]5-HTP (60 minutes) after different treatments. Scans included arterial blood sampling and metabolite analysis. 5-HT synthesis rates were calculated by a two-tissue compartment model (2TCM) with irreversible tracer trapping or Patlak analysis. Carbidopa (inhibitor peripheral AADC) dose-dependently increased [(11)C]5-HTP brain uptake, but did not influence 2TCM parameters. Therefore, 10 mg/kg carbidopa was applied in all subsequent study groups. These groups included treatment with NSD 1015 (general AADC inhibitor) or p-chlorophenylalanine (PCPA, inhibitor of tryptophan hydroxylase, TPH). In addition, the effect of a low-tryptophan (Trp) diet was investigated. NSD 1015 or Trp depletion did not affect any model parameters, but PCPA reduced [(11)C]5-HTP uptake, and the k3. This was unexpected as NSD 1015 directly inhibits the enzyme converting [(11)C]5-HTP to [(11)C]5-HT, suggesting that trapping of radioactivity does not distinguish between parent tracer and its metabolites. As different results have been acquired in monkeys and humans, [(11)C]5-HTP-PET may be suitable for measuring 5-HT synthesis in primates, but not in rodents.

Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds

“…Preclinical experiments with [ 11 C] 5 -HTP have been performed to study AADC activity/serotonin synthesis in the rhesus monkey, ,− rat, − and mice . A study of [ β - 11 C]­HTP metabolism in monkeys found that the parent fraction in plasma gradually decreased to ∼50% at 60 min, with [ 11 C]­hydroxyindoleacetic acid ([ 11 C]­HIAA) being the major metabolite (39%) .…”

Non-FDG PET/CT in Diagnostic Oncology: a pictorial review

“…47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,and 65) In the management of NETs 68 Ga-DOTA-conjugated peptide, PET/CT is used to localise primary tumours and detect sites of metastatic disease (staging); follow-up patients with known disease to detect residual, recurrent or progressive disease (restaging); determine somatostatin status; monitor response to therapy; and select patients with metastatic disease for peptide receptor radionuclide therapy (Skoura et al 2016;Sundin 2018;Singh et al 2018;Waseem et al 2019). Nitro-group are postulated to undergo reduction in hypoxic condition (pO2 ≤ 2-3 mmHg), forming highly reactive oxygen radicals that subsequently bind covalently to macromolecules inside the cells (Visser et al 2014;Orlefors et al 2005 (Fig. 67) PET-CT with 18 F-FMISO is a non-invasive method for detecting and characterising hypoxia in several tumours.…”

“…Nitro-group are postulated to undergo reduction in hypoxic condition (pO2 ≤ 2–3 mmHg), forming highly reactive oxygen radicals that subsequently bind covalently to macromolecules inside the cells (Visser et al 2014 ; Orlefors et al 2005 ).…”

Role of Serotonin Transporter in Eye Development of Drosophila melanogaster

“…In the brain, serotonin (5-hydroxytryptamine, 5-HT), the core molecule of the system, acts as a neurotransmitter and is associated with the feeling of wellness and happiness [3]. Altered regulation of serotonin concentration in the brain has been recorded not only in a vast range of behavioral functions, such as wake/sleep states, appetite, and sexual behavior, but also in the causation of multiple severe psychotic disorders, such as depression, bipolar disorder, and schizophrenia [4,5]. Although the roles of serotonin in the brain have been intensively investigated, the serotonergic function in peripheral organs, where serotonin acts as a hormonal molecule, is mostly uninvestigated, even though 95% of the serotonin in the whole body is produced by the gastrointestinal tract [6].…”