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

• Published in: EJNMMI research Vol. 9; no. 1; pp. 1 - 8
• Main Authors: Lindberg, Anton, Arakawa, Ryosuke, Nogami, Tsuyoshi, Nag, Sangram, Schou, Magnus, Elmore, Charles S., Farde, Lars, Pike, Victor W., Halldin, Christer
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 21-11-2019; Springer Nature B.V; SpringerOpen
• Subjects: 5-HT1B; Affinity; Agonist; Antagonist; Binding; Brain; Cardiac Imaging; Change detection; Imaging; Ligands; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Nuclear Medicine; Oncology; Original Research; Orthopedics; PET; Positron emission; Radioligand; Radiology; Receptors; Sensitivity analysis; Tomography; Agonist; Radioligand; Antagonist; 5-HT; PET
• ISSN: 2191-219X; 2191-219X
• DOI: 10.1186/s13550-019-0570-1

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.