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

Abstract

INTRODUCTION:

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.

METHODS:

[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.

RESULTS:

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.

CONCLUSIONS:

[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.

• Authors: Anton Lindberg, Shuiyu Lu, Sangram Nag, Magnus Schou, Jeih-San Liow, Sami S Zoghbi, Michael P Frankland, Robert L Gladding, Cheryl L Morse, Akihiro Takano, Nahid Amini, Charles S Elmore, Yong Sok Lee, Robert B Innis, Christer Halldin, Victor W Pike
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 70 Pg. 1-13 (03 2019) ISSN: 1872-9614 [Electronic] United States
• PMID: 30811975 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Ligands
• Receptor, Serotonin, 5-HT1B
• Serotonin 5-HT1 Receptor Agonists

Topics

• Animals
• Brain (diagnostic imaging, metabolism)
• Chemistry Techniques, Synthetic
• Hydrophobic and Hydrophilic Interactions
• Image Processing, Computer-Assisted
• Ligands
• Macaca mulatta
• Positron-Emission Tomography (methods)
• Radiochemistry
• Rats
• Receptor, Serotonin, 5-HT1B (metabolism)
• Serotonin 5-HT1 Receptor Agonists (chemical synthesis, chemistry, metabolism, pharmacokinetics)