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

Abstract

The PET tracer [11C]5-hydroxytryptophan ([11C]5-HTP), which is converted to [11C]5-hydroxytryptamine ([11C]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 [11C]5-HTP in rat? Male rats were scanned with [11C]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 [11C]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 [11C]5-HTP uptake, and the k3. This was unexpected as NSD 1015 directly inhibits the enzyme converting [11C]5-HTP to [11C]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, [11C]5-HTP-PET may be suitable for measuring 5-HT synthesis in primates, but not in rodents.