A PET reporter ligand for quantitative imaging of gene expression in the brain
The lack of brain penetrant and biologically stable positron emission tomography reporter systems hampers the development of neurological disease models and the monitoring of gene delivery because existing approaches depend on endogenous receptors that vary unpredictably in pathology. HaloTag, a fully exogenous protein label that forms rapid and irreversible bonds with synthetic ligands, provides a modular platform for engineering reporter probes with defined chemical properties. Here we developed a fluorine-18-labelled small-molecule HaloTag ligand optimized for brain entry and covalent retention at the reporter. The tracer showed specific binding in human cells expressing HaloTag and enabled non-invasive imaging of viral gene transfer to striatal neurons in mice, with clear detection of reporter expressing tissue and rapid clearance from surrounding regions. Optical imaging confirmed viral distribution and reporter expression, and a transgenic model expressing HaloTag fused to a postsynaptic protein demonstrated detection of physiologically expressed intraneuronal targets. This system establishes a modular platform for validating preclinical models and quantifying gene expression in the living brain.
Authors
- Jacqueline Berner (ORCID: https://orcid.org/0000-0002-9056-8745)
- Michael Lämmerhofer (ORCID: https://orcid.org/0000-0002-1318-0974)
- Seth G. N. Grant (ORCID: https://orcid.org/0000-0001-8732-8735)
- Bernd J. Pichler (ORCID: https://orcid.org/0000-0001-6784-5524)
- Bettina Weigelin (ORCID: https://orcid.org/0000-0003-4460-3113)
- Andreas Maurer (ORCID: https://orcid.org/0000-0003-2412-5361)
- Gina Dunkel
- Philipp Seyfried
- Johannes Kinzler
- Martin Schaller (ORCID: https://orcid.org/0000-0002-7930-1919)
- Sophie Stotz (ORCID: https://orcid.org/0000-0003-4020-1088)
- Kristina Herfert (ORCID: https://orcid.org/0000-0003-0231-7717)
- Sabrina Haas (ORCID: https://orcid.org/0009-0006-9003-8708)
Institutions
- University of Copenhagen (DK)
- Siemens (Germany) (DE)
- German Cancer Research Center (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- University of Tübingen (DE)
- IT University of Copenhagen (DK)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Biomedical Engineering
- Published
- 2026-07-27
- DOI
- https://doi.org/10.1038/s41551-026-01748-x
- Primary Topic
- Virus-based gene therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Eberhard Karls Universität Tübingen
- Novo Nordisk
- Faculty of Health and Medical Sciences, University of Western Australia
- Novo Nordisk Fonden
- Det Sundhedsvidenskabelige Fakultet, Københavns Universitet