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Fenfluramine evokes 5-HT2A receptor-mediated responses but does not displace [11C]MDL 100907: small animal PET and
Ella Hirani1, Trevor Sharp, Marie Sprakes
1Imaging Research Solutions Ltd., Cyclotron Building, London W12 0NN, UK. ella.hirani@ic.ac.uk
Abstract:
The in vivo binding of the 5-HT(2A) receptor-selective positron emission tomography (PET) ligand [(11)C]MDL 100907 and its sensitivity to endogenous 5-HT were quantified in rat brain using quad-HIDAC, a novel high-resolution PET camera for small animals. Specific binding of [(11)C]MDL 100907, estimated using volume of interest (VOI) to cerebellum ratios, corresponded well with both the known distribution of 5-HT(2A) receptors and tissue:cerebellum ratios obtained using ex vivo dissection. Specific binding was blocked by predosing with either nonradioactive MDL 100907 (0.2 or 0.4 mg/kg i.v.) or the 5-HT(2A/2C) receptor antagonist ketanserin (2 mg/kg i.v.), but was unaffected in rats pretreated with the 5-HT releasing agent, fenfluramine (10 mg/kg i.p.). In parallel studies, the same dose of fenfluramine was shown to be sufficient to cause an increase in the expression of the immediate early genes (IEG) c-fos and Arc mRNA in cortical regions with high 5-HT(2A) receptor density. This increase was blocked by MDL 100907 (0.2 mg/kg i.v.), confirming a 5-HT(2A) receptor-mediated effect. The results demonstrate that PET with [(11)C]MDL 100907 is insensitive to an increased concentration of synaptic 5-HT, implying that the ligand can be used clinically to monitor 5-HT(2A) receptor function or dysfunction in disease or during therapy, without the need to consider concomitant changes in neurotransmitter concentration.
Insights
This study shows that the PET ligand [(11)C]MDL 100907 accurately measures 5-HT(2A) receptors in rats. The ligand
Area of Science:
- Neuroscience
- Radiochemistry
- Pharmacology
Background:
- Serotonin 5-HT(2A) receptors are crucial in brain function and targeted by various therapeutics.
- Positron Emission Tomography (PET) ligands are vital for in vivo receptor imaging.
- Assessing PET ligand stability against endogenous neurotransmitter fluctuations is critical for clinical translation.
Purpose of the Study:
- To quantify the in vivo binding of the 5-HT(2A) receptor-selective PET ligand [(11)C]MDL 100907 in rat brain.
- To evaluate the sensitivity of [(11)C]MDL 100907 binding to endogenous serotonin (5-HT) levels.
- To determine the suitability of [(11)C]MDL 100907 for clinical monitoring of 5-HT(2A) receptor status.
Main Methods:
- Utilized quad-HIGH-RESOLUTION PET imaging in rats to assess [(11)C]MDL 100907 binding.
- Compared PET-derived specific binding with ex vivo dissection data for validation.
- Administered receptor antagonists (MDL 100907, ketanserin) and a 5-HT releasing agent (fenfluramine) to assess binding specificity and sensitivity.
Main Results:
- Specific binding of [(11)C]MDL 100907 correlated well with known 5-HT(2A) receptor distribution.
- Binding was effectively blocked by MDL 100907 and ketanserin.
- [(11)C]MDL 100907 binding remained unaffected by fenfluramine-induced increases in synaptic 5-HT.
Conclusions:
- PET imaging with [(11)C]MDL 100907 provides a reliable measure of 5-HT(2A) receptor availability in vivo.
- The ligand demonstrates insensitivity to fluctuations in endogenous synaptic 5-HT concentrations.
- [(11)C]MDL 100907 is a promising PET tracer for clinical studies of 5-HT(2A) receptor function in neurological and psychiatric disorders.
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