2. Academic Validation
  3. Synthesis and Evaluation of a Novel PET Radioligand for Imaging Glutaminyl Cyclase Activity as a Biomarker for Detecting Alzheimer's Disease

Synthesis and Evaluation of a Novel PET Radioligand for Imaging Glutaminyl Cyclase Activity as a Biomarker for Detecting Alzheimer's Disease

  • ACS Sens. 2024 May 24;9(5):2605-2613. doi: 10.1021/acssensors.4c00313.
William J Behof 1 2,  Justin R Haynes 1 2,  Clayton A Whitmore 1 2,  Yiu-Yin Cheung 1 2,  Mohammed N Tantawy 1 2,  Todd E Peterson 1 2 3,  Printha Wijesinghe 4,  Joanne A Matsubara 4,  Wellington Pham 1 2 5 6 7 3 8 9
Affiliations

Affiliations

  • 1 Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 2 Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.
  • 3 Vanderbilt Ingram Cancer Center, Nashville, Tennessee 37232, United States.
  • 4 Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC V5Z3N9, Canada.
  • 5 Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 6 Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee 37212, United States.
  • 7 Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States.
  • 8 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 9 Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States.
PMID: 38718161 DOI: 10.1021/acssensors.4c00313
Abstract

Several new lines of research have demonstrated that a significant number of Amyloid-β peptides found in Alzheimer's disease (AD) are truncated and undergo post-translational modification by glutaminyl cyclase (QC) at the N-terminal. Notably, QC's products of Abeta-pE3 and Abeta-pE11 have been active targets for investigational drug development. This work describes the design, synthesis, characterization, and in vivo validation of a novel PET radioligand, [18F]PB0822, for targeted imaging of QC. We report herein a simplified and robust chemistry for the synthesis of the standard compound, [19F]PB0822, and the corresponding [18F]PB0822 radioligand. The PET probe was developed with 99.9% radiochemical purity, a molar activity of 965 Ci.mmol-1, and an IC50 of 56.3 nM, comparable to those of the parent PQ912 inhibitor (62.5 nM). Noninvasive PET imaging showed that the probe is distributed in the brain 5 min after intravenous injection. Further, in vivo PET imaging with [18F]PB0822 revealed that AD 5XFAD mice harbor significantly higher QC activity than WT counterparts. The data also suggested that QC activity is found across different brain regions of the tested Animals.

Keywords

Alzheimer’s disease; PET imaging; [18F]PB0822; glutaminyl cyclase; pyroglutamate Abeta.

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