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PreprintCC BYChemRxiv

Preclinical and Pilot Human Evaluation of [18F]NIDF-1, an N-Protonation-Guided Tau PET Tracer

  • Wantong Guo1,2
  • Yishuo Wang3,4
  • Yuying Li1,2
  • Xiaojun Zhang5,6
  • Nan Wu1,2
  • Qilei Zhang7,8
  • Xiao-xin Yan7,8
  • Jinming Zhang5,6
  • Shaobo Yao3,4
  • Mengchao Cui1,2,9
9 affiliations
  1. 1Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry
  2. 2Beijing Normal University
  3. 3Department of PET/CT Diagnostic
  4. 4Tianjin Medical University General Hospital
  5. 5Department of Nuclear Medicine
  6. 6Chinese PLA General Hospital
  7. 7Department of Anatomy and Neurobiology
  8. 8Central South University Xiangya School of Medicine
  9. 9Institute for Advanced Study
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Abstract

Hyperphosphorylated tau aggregates are a pathological hallmark of Alzheimer’s disease (AD) and an important target for positron emission tomography (PET) imaging. Guided by the hypothesis that N-protonation enables electrostatic interactions with negatively charged sites associated with tau hyperphosphorylation, we designed and synthesized a focused series of azaindole derivatives and identified NIDF-1 as a lead compound by competitive autoradiography on AD brain sections (IC50 = 22.1 ± 6.8 nM). NIDF-1 showed low amyloid-β (Aβ) cross-reactivity and limited off-target toward monoamine oxidases (MAO). [18F]NIDF-1 exhibited favorable brain kinetics in rodents, with an initial brain uptake of 7.57% ID/g in mice and a peak brain mean standardized uptake value (SUVmean) of 2.20 in Sprague–Dawley (SD) rats, followed by rapid clearance (2-to-60-min brain uptake ratios of 18.46 and 3.30, respectively). Autoradiography confirmed preferential binding to ADassociated tau pathology. In a pilot human PET study, [18F]NIDF-1 showed higher cortical retention in an AD participant than in a healthy control. These findings identify [18F]NIDF-1 as a promising tau PET tracer with favorable tau binding affinity, brain kinetics, and encouraging initial human imaging results, while supporting N-protonation as a useful design consideration for tau-targeted imaging agents. KEYWORDS: N-Protonation, Tau PET tracer, Azaindole, Alzheimer’s disease

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Cite

BibTeXRIS
BibTeX
@misc{guo2026preclinical,
  title = {{Preclinical and Pilot Human Evaluation of [18F]NIDF-1, an N-Protonation-Guided Tau PET Tracer}},
  author = {Wantong Guo and Yishuo Wang and Yuying Li and Xiaojun Zhang and Nan Wu and Qilei Zhang and Xiao-xin Yan and Jinming Zhang and Shaobo Yao and Mengchao Cui},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15009101/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009101/v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Preclinical and Pilot Human Evaluation of [18F]NIDF-1, an N-Protonation-Guided Tau PET Tracer
AU  - Wantong Guo
AU  - Yishuo Wang
AU  - Yuying Li
AU  - Xiaojun Zhang
AU  - Nan Wu
AU  - Qilei Zhang
AU  - Xiao-xin Yan
AU  - Jinming Zhang
AU  - Shaobo Yao
AU  - Mengchao Cui
PY  - 2026
DA  - 2026/09/20
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15009101/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009101/v1
AB  - Hyperphosphorylated tau aggregates are a pathological hallmark of Alzheimer’s disease (AD) and an important target for positron emission tomography (PET) imaging. Guided by the hypothesis that N-protonation enables electrostatic interactions with negatively charged sites associated with tau hyperphosphorylation, we designed and synthesized a focused series of azaindole derivatives and identified NIDF-1 as a lead compound by competitive autoradiography on AD brain sections (IC50 = 22.1 ± 6.8 nM). NIDF-1 showed low amyloid-β (Aβ) cross-reactivity and limited off-target toward monoamine oxidases (MAO). [18F]NIDF-1 exhibited favorable brain kinetics in rodents, with an initial brain uptake of 7.57% ID/g in mice and a peak brain mean standardized uptake value (SUVmean) of 2.20 in Sprague–Dawley (SD) rats, followed by rapid clearance (2-to-60-min brain uptake ratios of 18.46 and 3.30, respectively). Autoradiography confirmed preferential binding to ADassociated tau pathology. In a pilot human PET study, [18F]NIDF-1 showed higher cortical retention in an AD participant than in a healthy control. These findings identify [18F]NIDF-1 as a promising tau PET tracer with favorable tau binding affinity, brain kinetics, and encouraging initial human imaging results, while supporting N-protonation as a useful design consideration for tau-targeted imaging agents. KEYWORDS: N-Protonation, Tau PET tracer, Azaindole, Alzheimer’s disease
ER  -