title: Synthesis, fluorine-18 radiolabeling, and in vitro characterization of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinoline carboxamide derivatives as potential PET radioligands for imaging peripheral benzodiazepine receptor.
abstract: The isoquinoline carboxamide derivative 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide (PK11195) has been shown to bind strongly and selectively to the peripheral benzodiazepine receptor (PBR) binding sites. A series of PK11195 analogues have been synthesized and biologically characterized. The affinities of the analogues for the PBR were determined using in vitro competitive binding assays with [(3)H]PK11195 in rat kidney mitochondrial membranes. The results showed that the 1-(2-iodophenyl)-N-methyl-N-(3-fluoropropyl)-3-isoquinoline carboxamide (9a) was the most potent compound (K(i)=0.26nM) of this series and is an excellent lead ligand for additional studies for labeling with fluorine-18 to determine whether it possesses the desired in vivo performance in non-human primates by PET imaging. Thus, radiolabeling of 9a with fluorine-18 was developed.
authors.affiliation: Department of Radiology, School of Medicine, Emory University, Atlanta, GA 30322, USA.
authors.forename: Weiping
authors.initials: W
authors.lastname: Yu
authors.forename: Eric
authors.initials: E
authors.lastname: Wang
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Voll
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Miller
authors.forename: Mark M
authors.initials: MM
authors.lastname: Goodman
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D005462:Fluorine Radioisotopes; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D007668:Kidney / Q000737:chemistry / Q000000981:diagnostic imaging / Q000187:drug effects; D008024:Ligands; D051336:Mitochondrial Membranes / Q000737:chemistry / Q000000981:diagnostic imaging / Q000187:drug effects; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D051381:Rats; D011963:Receptors, GABA-A / Q000032:analysis* / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; D007546:Isoquinolines; D008024:Ligands; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A; C037850:PK 11195