[(11)C]5-HTP and microPET are not suitable for pharmacodynamic studies in the rodent brainVisser, A. K. D., Ramakrishnan, N. K., Willemsen, A. T. M., Di Gialleonardo, V., de Vries, E. F. J., Kema, I. P., Dierckx, R. A. J. O. & van Waarde, A., Jan-2014, In : Journal of Cerebral Blood Flow and Metabolism. 34, 1, p. 118-125 8 p.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||8|
|Journal||Journal of Cerebral Blood Flow and Metabolism|
|Early online date||2-Oct-2013|
|Publication status||Published - Jan-2014|
- 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