[11C]AZ10419369: A selective 5-HT1B receptor radioligand suitable for positron emission tomography (PET); Characterization in cynomolgus monkey brain
Introduction
The serotonin 1B receptor (5-HT1B) has been implicated in several psychiatric disorders and is a potential pharmacological target in the treatment of depression. To date, there are no useful tools to image this receptor in vivo by positron emission tomography (PET). Here we report the radiosynthesis of a novel positron emission tomography (PET) radioligand, [11C]AZ10419369 (5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide) and its in vivo visualization of 5-HT1B receptors in the cynomolgus monkey brain.
Section snippets
Methods
AZ10419369 was readily labeled by N-methylation using [11C]methyl triflate, giving a radiochemical purity of > 99% and specific radioactivity of > 6000 Ci/mmol at the time of administration. [11C]AZ10419369 was evaluated with a total of five PET measurements in two cynomolgus macaques. The regional brain distribution was evaluated in baseline condition and specific binding was examined after pretreatment with a selective 5-HT1B antagonist, AR-A000002 (0.25 mg/kg, 1.0 mg/kg and 2.0 mg/kg).
Results
[11C]AZ10419369 passes into the primate brain rapidly and to a high extent (3–4% of injected dose). Highest uptake of radioactivity was observed in the occipital cortex and striatopallidal complex. Radioactivity uptake was moderate in thalamus and the frontal cortex regions and lowest in the cerebellum. Region over cerebellum ratios of [11C]AZ10419369 were 4.2 for the occipital cortex, 4.1 for the striatopallidal complex, and 2.6 for the thalamus and the frontal cortex. Pre-treatment with the
Conclusion
These data support the radioligand [11C]AZ10419369 as a suitable ligand for PET determination of 5-HT1B binding in vivo.