{
  "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",
  "abstract_shown": true,
  "affiliations": [
    "Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry",
    "Beijing Normal University",
    "Department of PET/CT Diagnostic",
    "Tianjin Medical University General Hospital",
    "Department of Nuclear Medicine",
    "Chinese PLA General Hospital",
    "Department of Anatomy and Neurobiology",
    "Central South University Xiangya School of Medicine",
    "Institute for Advanced Study"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Wantong Guo"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Yishuo Wang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yuying Li"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Xiaojun Zhang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Nan Wu"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Qilei Zhang"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Xiao-xin Yan"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Jinming Zhang"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Shaobo Yao"
    },
    {
      "affs": [
        0,
        1,
        8
      ],
      "name": "Mengchao Cui",
      "orcid": "0000-0002-3488-7864"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2q47q7ftwpy13.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15009101/v1",
  "fulltext_url": null,
  "id": "2q47q7ftwpy13",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009101/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7213892747",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15009101/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-20",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/2q47q7ftwpy13.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:19Z",
      "native_id": "10.26434/chemrxiv.15009101",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009101/v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
    }
  ],
  "title": "Preclinical and Pilot Human Evaluation of [18F]NIDF-1, an N-Protonation-Guided Tau PET Tracer",
  "title_text": "Preclinical and Pilot Human Evaluation of [18F]NIDF-1, an N-Protonation-Guided Tau PET Tracer",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:19Z",
  "url": "https://research.draconitic.com/paper/2q47q7ftwpy13",
  "venue": "ChemRxiv",
  "versions": []
}