RT Journal Article
SR Electronic
T1 AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 327
OP 337
DO 10.1124/jpet.114.220517
VO 352
IS 2
A1 Hang Chen
A1 Dianna Lester-Zeiner
A1 Jianxia Shi
A1 Silke Miller
A1 Charlie Glaus
A1 Essa Hu
A1 Ning Chen
A1 Jessica Able
A1 Christopher Biorn
A1 Jamie Wong
A1 Ji Ma
A1 Klaus Michelsen
A1 Geraldine Hill Della Puppa
A1 Tim Kazules
A1 Hui Hannah Dou
A1 Santosh Talreja
A1 Xiaoning Zhao
A1 Ada Chen
A1 Shannon Rumfelt
A1 Roxanne K. Kunz
A1 Hu Ye
A1 Oliver R. Thiel
A1 Toni Williamson
A1 Carl Davis
A1 Amy Porter
A1 David Immke
A1 Jennifer R. Allen
A1 James Treanor
YR 2015
UL http://jpet.aspetjournals.org/content/352/2/327.abstract
AB Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington’s disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography–tandem mass spectrometry technology. [3H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [18F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.