Synthesis and evaluation of two new candidate high-affinity full agonist PET radioligands for imaging 5-HT1B receptors

• Published in: Nuclear medicine and biology Vol. 70; pp. 1 - 13
• Main Authors: Lindberg, Anton, Lu, Shuiyu, Nag, Sangram, Schou, Magnus, Liow, Jeih-San, Zoghbi, Sami S., Frankland, Michael P., Gladding, Robert L., Morse, Cheryl L., Takano, Akihiro, Amini, Nahid, Elmore, Charles S., Lee, Yong Sok, Innis, Robert B., Halldin, Christer, Pike, Victor W.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Inc 01.03.2019; Elsevier BV
• Subjects: Affinity; Agonist; Agonists; Anxiety; Binding; Brain; Carbon monoxide; Carbon-11; Carbonylation; Efflux; Experiments; Headache; Intravenous administration; Mental depression; Methylation; Migraine; Neuroimaging; Parameter identification; Pharmacology; Physiochemistry; Positron emission; Positron emission tomography; Precursors; Pretreatment; Primates; Radioactivity; Radiochemistry; Radioisotopes; Radioligand; Receptors; Serotonin; Serotonin S1 receptors; Serotonin subtype 1B receptor; Tomography; Serotonin subtype 1B receptor; Agonist; Carbonylation; Radioligand; Carbon-11
• ISSN: 0969-8051; 1872-9614; 1872-9614
• DOI: 10.1016/j.nucmedbio.2019.01.005

The serotonin 1B receptor subtype is of interest in the pathophysiology and treatment of depression, anxiety, and migraine. Over recent years 5-HT1B receptor binding in human brain has been examined with PET using radioligands that are partial but not full agonists. To explore how the intrinsic activity of a PET radioligand may affect imaging performance, two high-affinity full 5-HT1B receptor agonists (AZ11136118, 4; and AZ11895987, 5) were selected from a large compound library and radiolabeled for PET examination in non-human primates. [11C]4 was obtained through Pd(0)-mediated insertion of [11C]carbon monoxide between prepared iodoarene and homochiral amine precursors. [11C]5 was obtained through N-11C-methylation of N-desmethyl precursor 6 with [11C]methyl triflate. [11C]4 and [11C]5 were studied with PET in rhesus or cynomolgus monkey. [11C]4 was studied with PET in mice and rats to measure brain uptake and specific binding. Ex-vivo experiments in rats were performed to identify whether there were radiometabolites in brain. Physiochemical parameters for [11C]4 (pKa, logD and conformational energetics) were evaluated. Both [11C]4 and [11C]5 were successfully produced in high radiochemical purity and in adequate amounts for PET experiments. After intravenous injection of [11C]4, brain radioactivity peaked at a low level (0.2 SUV). Pretreatment with tariquidar, an inhibitor of the brain P-gp efflux transporter, increased brain exposure four-fold whereas pretreatment with a high pharmacological dose of the 5-HT1B antagonist, AR-A000002, had no effect on the binding. Ex-vivo experiments in rats showed no radiometabolites entering brain. [11C]5 also failed to enter monkey brain under baseline conditions. [11C]4 and [11C]5 show too low brain uptake and specific binding to be useful PET radioligands. Low brain uptake is partly ascribed to efflux transporter action as well as unfavorable conformations.