Rapid Identification of a Novel Small Molecule Phosphodiesterase 10A (PDE10A) Tracer

• Published in: Journal of medicinal chemistry 2012-05, Vol.55 (10), p.4776-4787
• Main Authors: Hu, Essa, Ma, Ji, Biorn, Christopher, Lester-Zeiner, Dianna, Cho, Robert, Rumfelt, Shannon, Kunz, Roxanne K, Nixey, Thomas, Michelsen, Klaus, Miller, Silke, Shi, Jianxia, Wong, Jamie, Hill Della Puppa, Geraldine, Able, Jessica, Talreja, Santosh, Hwang, Dah-Ren, Hitchcock, Stephen A, Porter, Amy, Immke, David, Allen, Jennifer R, Treanor, James, Chen, Hang
• Format: Article
• Language: English
• Subjects: Aminopyridines - chemical synthesis; Aminopyridines - chemistry; Aminopyridines - pharmacokinetics; Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Brain - diagnostic imaging; Brain - enzymology; Cell Line; Chromatography, Liquid; Dogs; Humans; In Vitro Techniques; Male; Permeability; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacokinetics; Phosphoric Diester Hydrolases - metabolism; Protein Binding; Pyrazoles - pharmacokinetics; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacokinetics; Quinolines - pharmacokinetics; Radionuclide Imaging; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Rats; Rats, Sprague-Dawley; Stereoisomerism; Surface Plasmon Resonance; Tandem Mass Spectrometry; Tissue Distribution; Tritium
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm3002372

A radiolabeled tracer for imaging therapeutic targets in the brain is a valuable tool for lead optimization in CNS drug discovery and for dose selection in clinical development. We report the rapid identification of a novel phosphodiesterase 10A (PDE10A) tracer candidate using a LC–MS/MS technology. This structurally distinct PDE10A tracer, AMG-7980 (5), has been shown to have good uptake in the striatum (1.2% ID/g tissue), high specificity (striatum/thalamus ratio of 10), and saturable binding in vivo. The PDE10A affinity (K D) and PDE10A target density (B max) were determined to be 0.94 nM and 2.3 pmol/mg protein, respectively, using [3H]5 on rat striatum homogenate. Autoradiography on rat brain sections indicated that the tracer signal was consistent with known PDE10A expression pattern. The specific binding of [3H]5 to rat brain was blocked by another structurally distinct, published PDE10A inhibitor, MP-10. Lastly, our tracer was used to measure in vivo PDE10A target occupancy of a PDE10A inhibitor in rats using LC–MS/MS technology.