11C-Labeling of Aryl Ketones as Candidate Histamine Subtype-3 Receptor PET Radioligands through Pd(0)-Mediated 11C-Carbonylative Coupling.

Fabrice Siméon,Shuiyu Lu,William Culligan,Victor Pike

doi:10.3390/molecules22050792

Abstract

Pd(0)-mediated coupling between iodoarenes, [11C]carbon monoxide and aryltributylstannanes has been used to prepare simple model [11C]aryl ketones. Here, we aimed to label four 2-aminoethylbenzofuran chemotype based molecules ([11C]1–4) in the carbonyl position, as prospective positron emission tomography (PET) radioligands for the histamine subtype 3 receptor (H3R) by adapting this methodology with use of aryltrimethylstannanes. Radiosynthesis was successfully performed on a platform equipped with a mini-autoclave and a liquid handling robotic arm, within a lead-shielded hot-cell. Candidate radioligands were readily formulated in saline containing ethanol (10%, v/v) and ascorbic acid (0.5 mg/10 mL). Yields for preclinical use were in the range of 5–9%, decay-corrected from cyclotron-produced [11C]CO2 and molar activities were >115 GBq/µmol at end of synthesis. Radiochemical purities exceeded >97%.

Highlights

Histamine subtype-3 receptors (H3Rs) are located on presynaptic nerve terminals where they regulate the synthesis and release of histamine and modulate the release of other neurotransmitters, notably dopamine, serotonin, norepinephrine and γ-aminobutyric acid [1,2]
Several 18 F (t1/2 = 109.8 min) and 11 C (t1/2 = 20.4 min) labeled H3R radioligands have emerged based on imidazole and on non-imidazole chemotypes [5,6,7,8,9]
positron emission tomography (PET) radioligands for H3R based on a 2-aminoethylbenzofuran chemotype, we recently reported the

Summary

Introduction

Histamine subtype-3 receptors (H3Rs) are located on presynaptic nerve terminals where they regulate the synthesis and release of histamine and modulate the release of other neurotransmitters, notably dopamine, serotonin, norepinephrine and γ-aminobutyric acid [1,2]. H3R inverse agonists are a source of leads for developing positron emission tomography (PET) radioligands for H3R, which could be powerful tools for (i) elucidating differences in H3R distribution and density between healthy and disease states; and (ii) for determining the dose-dependence and duration of brain H3R receptor occupancy by drug candidates. Several 18 F (t1/2 = 109.8 min) and 11 C (t1/2 = 20.4 min) labeled H3R radioligands have emerged based on imidazole and on non-imidazole chemotypes [5,6,7,8,9]. The non-imidazole chemotype has provided radioligands with imaging performance in non-human primates and human subjects superior to that of the imidazole chemotype.

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Methods

Results