Characterization of the binding properties of T-773 as a PET radioligand for phosphodiesterase 10A.
Nucl Med Biol
; 42(2): 146-54, 2015 Feb.
Article
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| MEDLINE
| ID: mdl-25451212
ABSTRACT
INTRODUCTION:
Phosphodiesterase 10A (PDE10A) is a dual-substrate PDE that hydrolyzes both cAMP and cGMP and is selectively expressed in striatal medium spiny neurons. Recent studies have suggested that PDE10A inhibition is a novel approach for the treatment of disorders such as schizophrenia and Huntington's disease. A positron emission tomography (PET) occupancy study can provide useful information for the development of PDE10A inhibitors. We discovered T-773 as a candidate PET radioligand for PDE10A and investigated its properties by in vitro autoradiography and a PET study in a monkey.METHODS:
Profiling of T-773 as a PET radioligand for PDE10A was conducted by in vitro enzyme inhibitory assay, in vitro autoradiography, and PET study in a monkey.RESULTS:
T-773 showed a high binding affinity and selectivity for human recombinant PDE10A2 in vitro; the IC50 value in an enzyme inhibitory assay was 0.77nmol/L, and selectivity over other PDEs was more than 2500-fold. In autoradiography studies using mouse, rat, monkey, or human brain sections, radiolabeled T-773 selectively accumulated in the striatum. This selective accumulation was not observed in the brain sections of Pde10a-KO mice. The binding of [(3)H]T-773 to PDE10A in rat brain sections was competitively inhibited by MP-10, a selective PDE10A inhibitor. In rat brain sections, [(3)H]T-773 bound to a single high affinity site of PDE10A with Kd values of 12.2±2.2 and 4.7±1.2nmol/L in the caudate-putamen and nucleus accumbens, respectively. In a monkey PET study, [(11)C]T-773 showed good brain penetration and striatum-selective accumulation.CONCLUSION:
These results suggest that [(11)C]T-773 is a potential PET radioligand for PDE10A.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Inhibidores de Fosfodiesterasa
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Pirazoles
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Piridazinas
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Hidrolasas Diéster Fosfóricas
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Tomografía de Emisión de Positrones
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Nucl Med Biol
Asunto de la revista:
BIOLOGIA
/
MEDICINA NUCLEAR
Año:
2015
Tipo del documento:
Article
País de afiliación:
Japón