Synthesis and evaluation in monkey of two sensitive 11C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo.
We sought to develop (11)C-labeled ligands for sensitive imaging of brain peripheral benzodiazepine receptors (PBR) in vivo. Two aryloxyanilides with high affinity for PBR were identified and synthesized, namely, N-acetyl- N-(2-methoxycarbonylbenzyl)-2-phenoxyaniline ( 3, PBR01) and N-(2-methoxybenzyl)- N-(4-phenoxypyridin-3-yl)acetamide ( 10, PBR28). 3 was hydrolyzed to 4, which was esterified with [ (11)C]iodomethane to provide [ (11)C] 3. The O-desmethyl analogue of 10 was converted into [ (11)C] 10 with [ (11)C]iodomethane. [ (11)C] 3 and [ (11)C] 10 were each injected into monkey to assess their brain kinetics with positron emission tomography (PET). After administration of either radioligand there was moderately high brain uptake of radioactivity. Receptor blocking and displacement experiments showed that a high proportion of this radioactivity was bound specifically to PBR. In monkey and rat, 3 and 10 were rapidly metabolized by ester hydrolysis and N-debenzylation, respectively, each to a single polar radiometabolite. [ (11)C] 3 and [ (11)C] 10 are effective for imaging PBR in monkey brain. [ (11)C] 10 especially warrants further evaluation in human subjects.
Briard
Emmanuelle
E
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
Zoghbi
Sami S
SS
Imaizumi
Masao
M
Gourley
Jonathan P
JP
Shetty
H Umesha
HU
Hong
Jinsoo
J
Cropley
Vanessa
V
Fujita
Masahiro
M
Innis
Robert B
RB
Pike
Victor W
VW
D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000083:Acetanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000813:Anilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D006801:Humans; D007553:Isotope Labeling; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013045:Species Specificity
D000081:Acetamides; D000083:Acetanilides; D000813:Anilides; D001565:Benzoates; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D008024:Ligands; C526798:N-(2-methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide; C526797:N-acetyl-N-(2-methoxycarbonylbenzyl)-2-phenoxyaniline; D011725:Pyridines; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A