[(11)C]5-HTP and microPET are not suitable for pharmacodynamic studies in the rodent brain

Anniek K D Visser, Nisha K Ramakrishnan, Antoon T M Willemsen, Valentina Di Gialleonardo, Erik F J de Vries, Ido P Kema, Rudi A J O Dierckx, Aren van Waarde

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8 Citations (Scopus)

Abstract

The PET tracer [C-11]5-hydroxytryptophan ([C-11]5-HTP), which is converted to [C-11]5-hydroxytryptamine ([C-11]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 [C-11]5-HTP in rat? Male rats were scanned with [C-11]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 [C-11]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 [C-11]5-HTP uptake, and the k(3). This was unexpected as NSD 1015 directly inhibits the enzyme converting [C-11]5-HTP to [C-11]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, [C-11]5-HTP-PET may be suitable for measuring 5-HT synthesis in primates, but not in rodents.

Original languageEnglish
Pages (from-to)118-125
Number of pages8
JournalJournal of Cerebral Blood Flow and Metabolism
Volume34
Issue number1
Early online date2-Oct-2013
DOIs
Publication statusPublished - Jan-2014

Keywords

  • 5-Hydroxytryptophan
  • Animals
  • Aromatic-L-Amino-Acid Decarboxylases
  • Brain
  • Carbidopa
  • Carbon Radioisotopes
  • Enzyme Inhibitors
  • Hydrazines
  • Male
  • Models, Biological
  • Positron-Emission Tomography
  • Rats
  • Rats, Wistar
  • Sensitivity and Specificity
  • Serotonin
  • Tissue Distribution
  • Tryptophan

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