Searching for new serotonin 1A receptor antagonist radiotracer

Synthesis, in vitro and in vivo evaluation of 11C-O-methylated arylpiperazines as potential serotonin 1A (5-HT_1A) receptor antagonist radiotracers

Vidya Narayanaswami, Junchao Tong, Ferdinando Fiorino, Beatrice Severino, Rosa Sparaco, Elisa Magli, Flavia Giordano, Peter M. Bloomfield, Jaya Prabhakaran3, J. John Mann, Neil Vasdev, Kenneth Dahl and S. Dileep Kumar

 https://doi.org/10.1186/s41181-020-00096-8

Peter M. Bloomfield and his colleague, Junchao Tong, from Centre for Addiction and Mental Health (CAMH), Toronto, Ontario have used Mediso nanoScan PET/MR 3T for testing candidate serotonin receptor radioligands in this publication. 

Summary

Clinical importance of 5-HT_1A receptors in the pathogenesis of several psychiatric and neurodegenerative disorders has promoted development of carbon-11 and fluorine-18 labeled radiotracers for in vivo positron emission tomography (PET). The gold standard PET imaging agent limited its widespread use. 

The purpose of the current study was to develop and characterize a radioligand with suitable characteristics for imaging 5-HT_1A receptors in the brain. The authors have reported the in vitro pharmacological characterization, radiosynthesis and preliminary in vivo PET imaging of three new 5-HT_1A receptor arylpiperazine based ligands in rats (DF-100 (1), DF-300 (2) and DF-400 (3)). 

They concluded DF-400 represents a promising O-methylated lead candidate which if subjected to structural alterations, may either lead to improved selectivity for 5-HT_1A receptors or may assist in the development of the first PET radioligand for α1-adrenergic receptors. 

Results from nanoScan PET/MRI 3T

• Dynamic PET studies in rats demonstrated negligible brain uptake of [11C] DF100 (1) and [11C] DF-300 (2). In contrast, significant brain uptake of [11C] DF400 (3) was observed.

Fig. 2 Uptake of [11C]3 (a); [11C]2 (b) and [11C]1 (c) in rat brain. Shown are TACs averaged for left and right brain (A: n = 3; B and C: n = 1) in SUV and summed (0–60 min) PET images in coronal, transverse and sagittal planes, respectively, through the thalamus. The spatially co-registered MR images (2D fast spin echo) show left-half ROIs including thalamus (blue), anterior cingulate cortex (red), hippocampus (green) and cerebellum (magenta) for the corresponding color-coded TACs

• Nevertheless, DF-400 displayed significant off-target binding attributed to α1-adrenergic receptors based on regional distribution (thalamus>hippocampus) and blocking studies

Fig. 2 Blocking of the uptake of [11C]3 in rat brain by WAY-100635 (a) and prazosin (b). Shown are TACs, averaged for left and right brain, (n = 1; solid: baseline; dashed: blocking) in SUV and summed (0–60 min) PET images in coronal, transverse and sagittal planes, respectively, through the thalamus at baseline and under blocking conditions. The three depicted left-half ROIs include thalamus (orange), hippocampus (red) and cerebellum (magenta) for the corresponding color-coded TACs