Synthesis and Initial Characterization of a Reversible, Selective 18F-Labeled Radiotracer for Human Butyrylcholinesterase

Christian Gentzsch, Xinyu Chen, Philipp Spatz, Urban Košak, Damijan Knez, Naoko Nose, Stanislav Gobec, Takahiro Higuchi, Michael Decker

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: A neuropathological hallmark of Alzheimer’s disease (AD) is the presence of amyloid-β (Aβ) plaques in the brain, which are observed in a significant number of cognitively normal, older adults as well. In AD, butyrylcholinesterase (BChE) becomes associated with Aβ aggregates, making it a promising target for imaging probes to support diagnosis of AD. In this study, we present the synthesis, radiochemistry, in vitro and preliminary ex and in vivo investigations of a selective, reversible BChE inhibitor as PET-tracer for evaluation as an AD diagnostic. Procedures: Radiolabeling of the inhibitor was achieved by fluorination of a respective tosylated precursor using K[18F]. IC50 values of the fluorinated compound were obtained in a colorimetric assay using recombinant, human (h) BChE. Dissociation constants were determined by measuring hBChE activity in the presence of different concentrations of inhibitor. Results: Radiofluorination of the tosylate precursor gave the desired radiotracer in an average radiochemical yield of 20 ± 3 %. Identity and > 95.5 % radiochemical purity were confirmed by HPLC and TLC autoradiography. The inhibitory potency determined in Ellman’s assay gave an IC50 value of 118.3 ± 19.6 nM. Dissociation constants measured in kinetic experiments revealed lower affinity of the inhibitor for binding to the acylated enzyme (K2 = 68.0 nM) in comparison to the free enzyme (K1 = 32.9 nM). Conclusions: The reversibly acting, selective radiotracer is synthetically easily accessible and retains promising activity and binding potential on hBChE. Radiosynthesis with 18F labeling of tosylates was feasible in a reasonable time frame and good radiochemical yield.

Original languageEnglish
Pages (from-to)505-515
Number of pages11
JournalMolecular Imaging and Biology
Volume23
Issue number4
DOIs
Publication statusPublished - Aug 2021
Externally publishedYes

Keywords

  • Alzheimer’s disease
  • Biodistribution
  • Enzyme inhibitor
  • Positron emission tomography
  • Quaternization

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Fingerprint

Dive into the research topics of 'Synthesis and Initial Characterization of a Reversible, Selective <sup>18</sup>F-Labeled Radiotracer for Human Butyrylcholinesterase'. Together they form a unique fingerprint.

Cite this