title: Radiolabeled cholinesterase substrates: in vitro methods for determining structure-activity relationships and identification of a positron emission tomography radiopharmaceutical for in vivo measurement of butyrylcholinesterase activity.
abstract: There is currently great interest in developing radiolabeled substrates for acetylcholinesterase and butyrylcholinesterase that would be useful in the in vivo imaging of patients with Alzheimer's disease. Using a simple in vitro spectrophotometric assay for determination of enzymatic cleavage rates, the structure-activity relationship for a short series of 1-methyl-4-piperidinyl esters was investigated. Relative enzymatic hydrolysis rates for the well-characterized 1-methyl-4-piperidinyl acetate, propionate, and i-butyrate esters were in agreement with literature values. The 4 and 5 carbon esters of 1-methyl-4-piperidinol were specific for butyrylcholinesterase and cleaved in the rank order n-valerate > n-butyrate >> 2-methylbutyrate, iso-valerate. These spectrophotometric results were also in agreement with in vitro hydrolysis rates in mouse blood and with in vivo regional retention of radioactivity in mouse brain of 11C-labeled analogs. Brain uptake and apparent enzymatic rate constants for 1-[11C]methyl-4-piperidinyl n-butyrate and n-valerate were calculated from in vivo measurements in M. nemistrina using positron emission tomography. Based on higher brain uptake of radioactivity and superior pharmacokinetics, 1-[11C]methyl-4-piperidinyl n-butyrate was identified as a new radiopharmaceutical for the in vivo measurement of butyrylcholinesterase activity.
authors.affiliation: Department of Radiology, University of Michigan Medical Center, Ann Arbor 48109-0028, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Snyder
authors.forename: N
authors.initials: N
authors.lastname: Gunupudi
authors.forename: P S
authors.initials: PS
authors.lastname: Sherman
authors.forename: E R
authors.initials: ER
authors.lastname: Butch
authors.forename: M B
authors.initials: MB
authors.lastname: Skaddan
authors.forename: M R
authors.initials: MR
authors.lastname: Kilbourn
authors.forename: R A
authors.initials: RA
authors.lastname: Koeppe
authors.forename: D E
authors.initials: DE
authors.lastname: Kuhl
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002087:Butyrates / Q000737:chemistry* / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000032:analysis* / Q000097:blood / Q000378:metabolism; D002250:Carbon Radioisotopes; D004952:Esters / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006868:Hydrolysis; D007700:Kinetics; D008254:Macaca nemestrina; D051379:Mice; D010880:Piperidines / Q000737:chemistry*; D011422:Propionates / Q000737:chemistry / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014055:Tomography, Emission-Computed; D014631:Valerates / Q000737:chemistry / Q000378:metabolism
chemical_list: C420915:1-methyl-4-piperidinyl n-butyrate; D002087:Butyrates; D002250:Carbon Radioisotopes; D004952:Esters; D010880:Piperidines; D011422:Propionates; D019275:Radiopharmaceuticals; D014631:Valerates; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase