Radiolabelling and PET brain imaging of the α1-adrenoceptor antagonist Lu AE43936.
Nucl Med Biol
; 40(1): 135-40, 2013 Jan.
Article
en En
| MEDLINE
| ID: mdl-23165140
ABSTRACT
Cerebral α1-adrenoceptors are a common target for many antipsychotic drugs. Thus, access to positron emission tomography (PET) brain imaging of α1-adrenoceptors could make important contributions to the understanding of psychotic disorders as well as to the pharmacokinetics and occupancy of drugs targeting the α1-adrenoceptors. However, so far no suitable PET radioligand has been developed for brain imaging of α1-adrenoceptors. Here, we report the synthesis of both enantiomers of the desmethyl precursors of the high affinity α1-adrenoceptor ligand (1). The two enantiomers of 1 were subsequently [¹¹C] radiolabelled and evaluated for brain uptake and binding by PET imaging in Danish Landrace pigs. (S)-[¹¹C]-1 and (R)-[¹¹C]-1 showed very limited brain uptake. Pre-treatment with cyclosporine A (CsA) resulted in a large increase in brain uptake, indicating that (R)-[¹¹C]-1 is a substrate for active efflux-transporters. This was confirmed in Madin Darby canine kidney (MDCK) cells overexpressing permeability glycoprotein (Pgp). In conclusion, the limited brain uptake of both (S)-[¹¹C]-1 and (R)-[¹¹C]-1 in the pig brain necessitates the search for alternative radioligands for in vivo PET brain imaging of α1-adrenoceptors.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Encéfalo
/
Receptores Adrenérgicos alfa 1
/
Tomografía de Emisión de Positrones
/
Dibenzotiepinas
/
Antagonistas de Receptores Adrenérgicos alfa 1
Límite:
Animals
Idioma:
En
Revista:
Nucl Med Biol
Asunto de la revista:
BIOLOGIA
/
MEDICINA NUCLEAR
Año:
2013
Tipo del documento:
Article
País de afiliación:
Dinamarca