Synthesis and Preliminary Evaluation of [11 C]GNE-1023 as a Potent PET Probe for Imaging Leucine-Rich Repeat Kinaseâ
2 (LRRK2) in Parkinson's Disease.
ChemMedChem
; 14(17): 1580-1585, 2019 09 04.
Article
em En
| MEDLINE
| ID: mdl-31365783
ABSTRACT
Leucine-rich repeat kinaseâ
2 (LRRK2) is a large protein involved in the pathogenesis of Parkinson's disease (PD). It has been demonstrated that PD is mainly conferred by LRRK2 mutations that bring about increased kinase activity. As a consequence, selective inhibition of LRRK2 may help to recover the normal functions of LRRK2, thereby serving as a promising alternative therapeutic target for PD treatment. The mapping of LRRK2 by positron emission tomography (PET) studies allows a thorough understanding of PD and other LRRK2-related disorders; it also helps to validate and translate novel LRRK2 inhibitors. However, no LRRK2 PET probes have yet been reported in the primary literature. Herein we present a facile synthesis and preliminary evaluation of [11 C]GNE-1023 as a novel potent PET probe for LRRK2 imaging in PD. [11 C]GNE-1023 was synthesized in good radiochemical yield (10 % non-decay-corrected RCY), excellent radiochemical purity (>99 %), and high molar activity (>37â
GBq µmol-1 ). Excellent inâ
vitro binding specificity of [11 C]GNE-1023 toward LRRK2 was demonstrated in cross-species studies, including rat and nonhuman primate brain tissues by autoradiography experiments. Subsequent whole-body biodistribution studies indicated limited brain uptake and urinary and hepatobiliary elimination of this radioligand. This study may pave the way for further development of a new generation of LRRK2 PET probes.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
/
Pirimidinas
/
Morfolinas
/
Compostos Radiofarmacêuticos
/
Inibidores de Proteínas Quinases
/
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
ChemMedChem
Assunto da revista:
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos