N-benzyl-2-(6,8-dichloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N-(6-(7-nitrobenzo[c][1,2,5]oxadiazol-4-ylamino)hexyl)acetamide as a new fluorescent probe for peripheral benzodiazepine receptor and microglial cell visualization.
The aim of this work was to develop new fluorescent probes for the localization and function of the peripheral benzodiazepine receptor (PBR). This receptor is primarily expressed on the mitochondria, and it is overexpressed in a variety of different states including glioma, breast cancer, Alzeheimer's disease, and activated microglia. For the mentioned purpose, imidazopyridine and imidazopyrimidine compounds 5-20 were synthesized, and their affinity for PBR was determined. Although some intrinsically fluorescent imidazopyrimidine compounds 12-20 possess good binding affinity, they cannot be used for visualizing PBR due to their unfavorable fluorescence characteristics. Among the imidazopyridine-7-nitrofurazan conjugates 5-11, compound 10 was the most active, and it was found to stain live Ra2 microglial cells effectively. An in vivo biodistribution study carried out on compound 10 showed that this imidazopyridine derivative, injected in the carotid artery, is able to penetrate to liver parenchyma, whereas fluorescein isothiocyanate labeled dextran (FITC-dextran), used as a control dye, hardly penetrated from blood vessels to tissues. On the other hand, as for the distribution to brain, the patterns of staining with 10 and FITC-dextran are similar, indicating that both of them hardly penetrate into the brain because of the existence of the blood-brain barrier. The obtained results indicate that compound 10 represents a new useful fluorescent probe for visualization of activated microglia and PBR.
Laquintana
Valentino
V
Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Via Orabona 4, 70125 Bari, Italy.
Denora
Nunzio
N
Lopedota
Angela
A
Suzuki
Hiromi
H
Sawada
Makoto
M
Serra
Mariangela
M
Biggio
Giovanni
G
Latrofa
Andrea
A
Trapani
Giuseppe
G
Liso
Gaetano
G
D009327:4-Chloro-7-nitrobenzofurazan / Q000737:chemistry*; D000081:Acetamides / Q000138:chemical synthesis*; D000544:Alzheimer Disease / Q000473:pathology; D001665:Binding Sites; D001943:Breast Neoplasms / Q000473:pathology; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D005456:Fluorescent Dyes / Q000138:chemical synthesis*; D005910:Glioma / Q000473:pathology; D007093:Imidazoles / Q000737:chemistry*; D008107:Liver Diseases / Q000473:pathology; D017628:Microglia / Q000166:cytology / Q000473:pathology* / Q000648:ultrastructure; D028361:Mitochondrial Diseases / Q000473:pathology; D011725:Pyridines / Q000737:chemistry*; D011963:Receptors, GABA-A / Q000032:analysis* / Q000378:metabolism
D000081:Acetamides; D005456:Fluorescent Dyes; D007093:Imidazoles; D011725:Pyridines; D011963:Receptors, GABA-A; D009327:4-Chloro-7-nitrobenzofurazan; D016650:Fluorescein-5-isothiocyanate; C023666:pyridine