Multiple strategies for the preparation of a sulfur-35 labeled NPC1L1 radioligand

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 17; pp. 5033 - 5036
• Main Authors: Simeone, Joseph P., Braun, Matthew P., Leone, Joseph F., Lin, Peter, DeVita, Robert J., Garcia-Calvo, Margarita, Bull, Herb G., Lisnock, JeanMarie, Dean, Dennis C.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-09-2009; Elsevier
• Subjects: Animals; Anticholesteremic Agents - chemical synthesis; Anticholesteremic Agents - chemistry; Anticholesteremic Agents - pharmacology; Azetidines - chemical synthesis; Azetidines - chemistry; Azetidines - pharmacology; Biological and medical sciences; Cell Line; Contrast media. Radiopharmaceuticals; Ezetimibe; Glucuronides - chemistry; Humans; Ligands; Medical sciences; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Mice; NPC1L1; Pharmacology. Drug treatments; Protein Binding; Radioligand; Rats; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - metabolism; Sulfur Radioisotopes - chemistry; Sulfur-35; Synthesis; Sulfur-35; Radioligand; Synthesis; NPC1L1; Sulfonamide; Acetylenic compound; Radiolabelling; Sulfur 35; Ligand; Metabolite; Lactam; Glucuroconjugate; Uronic acid; Fluorine Organic compounds; Chemical synthesis; Sulfur Isotopes
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.07.051

The discovery of a sulfur-35 labeled radioligand with high affinity for the NPC1L1 receptor across species is reported.
During our effort to design a receptor binding assay to aid in the elucidation of the molecular mechanism of ezetimibe, we prepared a sulfur-35 containing radioligand which exhibits improved potency over the glucuronide conjugate of ezetimibe in both native enterocyte brush border membranes and membranes from cells expressing recombinant NPC1L1. Herein, we describe the different synthetic strategies which were used to obtain this compound as well as its effectiveness in the aforementioned assay.