1. Department of Radiology, Division of Nuclear Medicine, University of Michigan Medical Center, Ann Arbor, U.S.A.
2. ^*Department of Chemistry, Eastern Michigan University, Ypsilanti, Michigan, U.S.A.

Correspondence: Scott E Snyder, Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical Center, B1G 412 University Hospital, Ann Arbor, MI 48109-0028, U.S.A.

Received 24 August 2000; Revised 16 October 2000; Accepted 17 October 2000.

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.