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Background  Over the last decade, a few radioligands have been developed for PET imaging of brain 5-HT 1B  receptors. The 5-HT 1B  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-HT 1B  receptor impacts on its ability to detect changes in endogenous synaptic 5-HT density. Three high-affinity  11 C-labeled 5-HT 1B  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 [ 11 C] 3 . The most antagonistic radioligand showed the lowest reduction in specific binding.    Conclusions  Three 5-HT 1B  PET radioligands were identified with differing intrinsic activity that could be used in imaging high- and low-affinity states of 5-HT 1B  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.

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