RESUMO
Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.
Assuntos
Encéfalo/ultraestrutura , Radioisótopos de Flúor/farmacocinética , Naftiridinas , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Receptor CB2 de Canabinoide/química , Animais , Células Cultivadas , Feminino , Humanos , Camundongos , Naftiridinas/síntese química , Naftiridinas/química , Ligação Proteica , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
The development of cannabinoid receptor type 2 (CB2R) radioligands for positron emission tomography (PET) imaging was intensively explored. To overcome the low metabolic stability and simultaneously increase the binding affinity of known CB2R radioligands, a carborane moiety was used as a bioisostere. Here we report the synthesis and characterization of carborane-based 1,8-naphthyridinones and thiazoles as novel CB2R ligands. All tested compounds showed low nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide (LUZ5) exhibiting the highest affinity (0.8 nM). Compound [18F]LUZ5-d8 was obtained with an automated radiosynthesizer in high radiochemical yield and purity. In vivo evaluation revealed the improved metabolic stability of [18F]LUZ5-d8 compared to that of [18F]JHU94620. PET experiments in rats revealed high uptake in spleen and low uptake in brain. Thus, the introduction of a carborane moiety is an appropriate tool for modifying literature-known CB2R ligands and gaining access to a new class of high-affinity CB2R ligands, while the in vivo pharmacology still needs to be addressed.
Assuntos
Encéfalo , Tomografia por Emissão de Pósitrons , Ratos , Animais , Ligantes , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ligação Proteica , Receptores de Canabinoides/metabolismoRESUMO
The cannabinoid receptor type 2 (CB2R) is an attractive target for the diagnosis and therapy of neurodegenerative diseases and cancer. In this study, we aimed at the development of a novel 18F-labeled radioligand starting from the structure of the known naphthyrid-2-one CB2R ligands. Compound 28 (LU13) was identified with the highest binding affinity and selectivity versus CB1R (CB2RKi = 0.6 nM; CB1RKi/CB2RKi > 1000) and was selected for radiolabeling with fluorine-18 and biological characterization. The new radioligand [18F]LU13 showed high CB2R affinity in vitro as well as high metabolic stability in vivo. PET imaging with [18F]LU13 in a rat model of vector-based/-related hCB2R overexpression in the striatum revealed a high signal-to-background ratio. Thus, [18F]LU13 is a novel and highly promising PET radioligand for the imaging of upregulated CB2R expression under pathological conditions in the brain.