[ 18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: Synthesis and in vivo evaluation in rhesus monkey

Eric D. Hostetler, Sandra Sanabria-Bohórquez, Hong Fan, Zhizhen Zeng, Linda Gammage, Patricia Miller, Stacey O'Malley, Brett Connolly, James Mulhearn, Scott T. Harrison, Scott E. Wolkenberg, James Barrow, David L. Williams, Richard J. Hargreaves, Cyrille Sur, Jacquelynn J. Cook

Research output: Contribution to journalArticle

Abstract

Introduction: An 18F-labeled positron emission tomography (PET) tracer for amyloid plaque is desirable for early diagnosis of Alzheimer's disease, particularly to enable preventative treatment once effective therapeutics are available. Similarly, such a tracer would be useful as a biomarker for enrollment of patients in clinical trials for evaluation of antiamyloid therapeutics. Furthermore, changes in the level of plaque burden as quantified by an amyloid plaque PET tracer may provide valuable insights into the effectiveness of amyloid-targeted therapeutics. This work describes our approach to evaluate and select a candidate PET tracer for in vivo quantification of human amyloid plaque. Methods: Ligands were evaluated for their in vitro binding to human amyloid plaques, lipophilicity and predicted blood-brain barrier permeability. Candidates with favorable in vitro properties were radiolabeled with 18F and evaluated in vivo. Baseline PET scans in rhesus monkey were conducted to evaluate the regional distribution and kinetics of each tracer using tracer kinetic modeling methods. High binding potential in cerebral white matter and cortical grey matter was considered an unfavorable feature of the candidate tracers. Results: [ 18F]MK-3328 showed the most favorable combination of low in vivo binding potential in white matter and cortical grey matter in rhesus monkeys, low lipophilicity (Log D=2.91) and high affinity for human amyloid plaques (IC 50=10.5±1.3 nM). Conclusions: [ 18F]MK-3328 was identified as a promising PET tracer for in vivo quantification of amyloid plaques, and further evaluation in humans is warranted.

Original languageEnglish (US)
Pages (from-to)1193-1203
Number of pages11
JournalNuclear Medicine and Biology
Volume38
Issue number8
DOIs
StatePublished - Nov 2011
Externally publishedYes

Fingerprint

Amyloid Plaques
Macaca mulatta
Positron-Emission Tomography
Therapeutics
Blood-Brain Barrier
Amyloid
Early Diagnosis
Permeability
Alzheimer Disease
Biomarkers
Clinical Trials
Ligands

Keywords

  • Alzheimer's disease
  • Amyloid plaque, PET
  • Fluorine-18
  • Monkey
  • White matter

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging

Cite this

Hostetler, E. D., Sanabria-Bohórquez, S., Fan, H., Zeng, Z., Gammage, L., Miller, P., ... Cook, J. J. (2011). [ 18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: Synthesis and in vivo evaluation in rhesus monkey. Nuclear Medicine and Biology, 38(8), 1193-1203. https://doi.org/10.1016/j.nucmedbio.2011.04.004

[ 18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers : Synthesis and in vivo evaluation in rhesus monkey. / Hostetler, Eric D.; Sanabria-Bohórquez, Sandra; Fan, Hong; Zeng, Zhizhen; Gammage, Linda; Miller, Patricia; O'Malley, Stacey; Connolly, Brett; Mulhearn, James; Harrison, Scott T.; Wolkenberg, Scott E.; Barrow, James; Williams, David L.; Hargreaves, Richard J.; Sur, Cyrille; Cook, Jacquelynn J.

In: Nuclear Medicine and Biology, Vol. 38, No. 8, 11.2011, p. 1193-1203.

Research output: Contribution to journalArticle

Hostetler, ED, Sanabria-Bohórquez, S, Fan, H, Zeng, Z, Gammage, L, Miller, P, O'Malley, S, Connolly, B, Mulhearn, J, Harrison, ST, Wolkenberg, SE, Barrow, J, Williams, DL, Hargreaves, RJ, Sur, C & Cook, JJ 2011, '[ 18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: Synthesis and in vivo evaluation in rhesus monkey', Nuclear Medicine and Biology, vol. 38, no. 8, pp. 1193-1203. https://doi.org/10.1016/j.nucmedbio.2011.04.004
Hostetler, Eric D. ; Sanabria-Bohórquez, Sandra ; Fan, Hong ; Zeng, Zhizhen ; Gammage, Linda ; Miller, Patricia ; O'Malley, Stacey ; Connolly, Brett ; Mulhearn, James ; Harrison, Scott T. ; Wolkenberg, Scott E. ; Barrow, James ; Williams, David L. ; Hargreaves, Richard J. ; Sur, Cyrille ; Cook, Jacquelynn J. / [ 18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers : Synthesis and in vivo evaluation in rhesus monkey. In: Nuclear Medicine and Biology. 2011 ; Vol. 38, No. 8. pp. 1193-1203.
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T1 - [ 18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers

T2 - Synthesis and in vivo evaluation in rhesus monkey

AU - Hostetler, Eric D.

AU - Sanabria-Bohórquez, Sandra

AU - Fan, Hong

AU - Zeng, Zhizhen

AU - Gammage, Linda

AU - Miller, Patricia

AU - O'Malley, Stacey

AU - Connolly, Brett

AU - Mulhearn, James

AU - Harrison, Scott T.

AU - Wolkenberg, Scott E.

AU - Barrow, James

AU - Williams, David L.

AU - Hargreaves, Richard J.

AU - Sur, Cyrille

AU - Cook, Jacquelynn J.

PY - 2011/11

Y1 - 2011/11

N2 - Introduction: An 18F-labeled positron emission tomography (PET) tracer for amyloid plaque is desirable for early diagnosis of Alzheimer's disease, particularly to enable preventative treatment once effective therapeutics are available. Similarly, such a tracer would be useful as a biomarker for enrollment of patients in clinical trials for evaluation of antiamyloid therapeutics. Furthermore, changes in the level of plaque burden as quantified by an amyloid plaque PET tracer may provide valuable insights into the effectiveness of amyloid-targeted therapeutics. This work describes our approach to evaluate and select a candidate PET tracer for in vivo quantification of human amyloid plaque. Methods: Ligands were evaluated for their in vitro binding to human amyloid plaques, lipophilicity and predicted blood-brain barrier permeability. Candidates with favorable in vitro properties were radiolabeled with 18F and evaluated in vivo. Baseline PET scans in rhesus monkey were conducted to evaluate the regional distribution and kinetics of each tracer using tracer kinetic modeling methods. High binding potential in cerebral white matter and cortical grey matter was considered an unfavorable feature of the candidate tracers. Results: [ 18F]MK-3328 showed the most favorable combination of low in vivo binding potential in white matter and cortical grey matter in rhesus monkeys, low lipophilicity (Log D=2.91) and high affinity for human amyloid plaques (IC 50=10.5±1.3 nM). Conclusions: [ 18F]MK-3328 was identified as a promising PET tracer for in vivo quantification of amyloid plaques, and further evaluation in humans is warranted.

AB - Introduction: An 18F-labeled positron emission tomography (PET) tracer for amyloid plaque is desirable for early diagnosis of Alzheimer's disease, particularly to enable preventative treatment once effective therapeutics are available. Similarly, such a tracer would be useful as a biomarker for enrollment of patients in clinical trials for evaluation of antiamyloid therapeutics. Furthermore, changes in the level of plaque burden as quantified by an amyloid plaque PET tracer may provide valuable insights into the effectiveness of amyloid-targeted therapeutics. This work describes our approach to evaluate and select a candidate PET tracer for in vivo quantification of human amyloid plaque. Methods: Ligands were evaluated for their in vitro binding to human amyloid plaques, lipophilicity and predicted blood-brain barrier permeability. Candidates with favorable in vitro properties were radiolabeled with 18F and evaluated in vivo. Baseline PET scans in rhesus monkey were conducted to evaluate the regional distribution and kinetics of each tracer using tracer kinetic modeling methods. High binding potential in cerebral white matter and cortical grey matter was considered an unfavorable feature of the candidate tracers. Results: [ 18F]MK-3328 showed the most favorable combination of low in vivo binding potential in white matter and cortical grey matter in rhesus monkeys, low lipophilicity (Log D=2.91) and high affinity for human amyloid plaques (IC 50=10.5±1.3 nM). Conclusions: [ 18F]MK-3328 was identified as a promising PET tracer for in vivo quantification of amyloid plaques, and further evaluation in humans is warranted.

KW - Alzheimer's disease

KW - Amyloid plaque, PET

KW - Fluorine-18

KW - Monkey

KW - White matter

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