Rapid identification of a novel small molecule phosphodiesterase 10A (PDE10A) tracer.
J Med Chem
; 55(10): 4776-87, 2012 May 24.
Article
em En
| MEDLINE
| ID: mdl-22548439
ABSTRACT
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 [(3)H]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 [(3)H]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.
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1
Base de dados:
MEDLINE
Assunto principal:
Piridazinas
/
Diester Fosfórico Hidrolases
/
Aminopiridinas
Tipo de estudo:
Diagnostic_studies
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article