Potential for imaging the high-affinity state of the 5-HT1B receptor: a comparison of three PET radioligands with differing intrinsic activity

Background Over the last decade, a few radioligands have been developed for PET imaging of brain 5-HT1B receptors. The 5-HT1B receptor is a G-protein-coupled receptor (GPCR) that exists in two different agonist affinity states. An agonist ligand is expected to be more sensitive towards competition from another agonist, such as endogenous 5-HT, than an antagonist ligand. It is of interest to know whether the intrinsic activity of a PET radioligand for the 5-HT1B receptor impacts on its ability to detect changes in endogenous synaptic 5-HT density. Three high-affinity 11C-labeled 5-HT1B PET radioligands with differing intrinsic activity were applied to PET measurements in cynomolgus monkey to evaluate their sensitivity to be displaced within the brain by endogenous 5-HT. For these experiments, fenfluramine was pre-administered at two different doses (1.0 and 5.0 mg/kg, i.v.) to induce synaptic 5-HT release. Results A dose-dependent response to fenfluramine was detected for all three radioligands. At the highest dose of fenfluramine (5.0 mg/kg, i.v.), reductions in specific binding in the occipital cortex increased with radioligand agonist efficacy, reaching 61% for [11C]3. The most antagonistic radioligand showed the lowest reduction in specific binding. Conclusions Three 5-HT1B PET radioligands were identified with differing intrinsic activity that could be used in imaging high- and low-affinity states of 5-HT1B receptors using PET. From this limited study, radioligand sensitivity to endogenous 5-HT appears to depend on agonist efficacy. More extensive studies are required to substantiate this suggestion.

Sodium and guanine nucleotide regulation of dopamine receptor agonist and antagonist binding sites in MtTW15 pituitary tumors

The modulation of the dopamine receptor in MtTW15 tumors was investigated. The antagonist dopaminergic binding site in MtTW15 tumors labelled with [3H]spiperone remains unchanged at 25 °C in the presence or absence of sodium or guanine nucleotides (Gpp(NH)p); by contrast at 37 °C sodium increases the affinity while Gpp(NH)p decreases it slightly. The dopamine receptor in this tumor, such as the intact adenohypophysis, exists in a high and low affinity state for dopamine agonists. These agonist affinity states evaluated with apomorphine competition for [3H]spiperone binding show similar affinities as those of intact tissue but have a lower proportion of the high affinity state. At 25 °C, a partial conversion of the high into the low affinity state is obtained in the presence of both sodium and Gpp(NH)p, while at 37 °C a complete conversion is observed. These data show differences in the modulation of antagonist and agonist dopaminergic binding sites in MtTW15 pituitary tumors compared with the intact pituitary.