Acute S-ketamine application does not alter cerebral [18F]altanserin binding: a pilot PET study in humans

Abstract

Modeling short-term psychotic states with subanaesthetic doses of ketamine provides substantial experimental evidence in support of the glutamate hypothesis of schizophrenia. Ketamine exerts its pharmacological effects both directly via interactions with glutamate receptors and indirectly by stimulating presynaptic release of endogenous serotonin (5-HT). The aim of this feasibility study was to examine whether acute ketamine-induced 5-HT release interferes with the binding of the 5-HT(2A) receptor (5-HT(2A)R) radioligand [(18)F]altanserin and positron emission tomography (PET). Two subjects treated with ketamine and one subject treated with placebo underwent [(18)F]altanserin PET at distribution equilibrium conditions. Robust physiological, psychopathological and cognitive effects were present at ketamine plasma concentrations exceeding 100 microg/l during >70 min. Notwithstanding, we observed stable radioligand binding (changes +/-95% CI of -1.0 +/- 1.6% and +4.1 +/- 1.8% versus -1.2 +/- 2.6%) in large cortical regions presenting high basal uptake of both, [(18)F]altanserin and ketamine. Marginal decreases of 4% of radioligand binding were observed in the frontal lobe, and 8% in a posteriorily specified frontomesial subregion. This finding is not compatible with a specific radioligand displacement from 5-HT(2A)R which should occur proportionally throughout the whole brain. Instead, the spatial pattern of these minor reductions was congruent with ketamine-induced increases in cerebral blood flow observed in a previous study using [(15)O]butanol PET. This may caused by accelerated clearance of unspecifically bound [(18)F]altanserin from cerebral tissue with increased perfusion. In conclusion, this study suggests that [(18)F]altanserin PET is not sensitive to acute neurotransmitter fluctuations under ketamine. Advantageously, the stability of [(18)F]altanserin PET towards acute influences is a prerequisite for its future use to detect sub-acute and chronic effects of ketamine.

5-HT2A receptor density is decreased in the at-risk mental state

“…Venous blood samples were taken at 2, 5, 10,20,30,45,60,120,130,140,150,160,170, and 180 min p.i. The fraction of radioactive parent compound in plasma was determined by selective liquidliquid extraction with quantitation of the recovery of total radioactivity, followed by thin-layer chromatography (Matusch et al 2007). …”

Fenfluramine‐induced serotonin release decreases [11C]AZ10419369 binding to 5‐HT1B‐receptors in the primate brain

“…Radioligands selectively targeting 5-HT 2A or 5-HT 4 However, PET studies have shown no evident susceptibility of these radioligands to modified serotonin level in rat 130,270 and human 169,199,207,254,306,349 . Currently, only [ 11 C]SB207145 is available for imaging of 5-HT 4 receptors using PET 197 , but citalopram did not modify [ 11 C]SB207145 binding in control subjects 198 .…”

S‐ketamine and GABA‐A‐receptor interaction in humans: an exploratory study with I‐123‐iomazenil SPECT

“…In a pilot study, Matusch et al (2007) could not demonstrate interaction of S-ketamine with F-18altanserin binding. However, due to their lower dosage of ketamine and a small number of subjects (ketamine ¼ 2, placebo ¼ 1) it cannot be excluded that a bigger sample size may lead to different results.…”