Re-defining the 3Rs of pre-clinical research in nuclear medicine

Pre-clinical nuclear medicine occupies a distinctive position in biomedical research, simultaneously driving radioligand discovery for diagnostic imaging and targeted radionuclide therapy while serving as a cross-disciplinary tool for investigating drug development, physiology, disease mechanisms and treatment response. These dual roles place significant ethical, operational and environmental demands on animal-based research. Although the classical 3Rs (replace, reduce and refine) remain foundational, rapid advances in theranostics, molecular targeting, high-content imaging and artificial intelligence have outpaced the traditional framework. Emerging capabilities such as in-silico biodistribution modelling, digital twins, ultra-low-dose AI-enhanced imaging, automated radiochemistry, distributed data analytics and alternative biological platforms now provide realistic opportunities to displace, minimise or ethically enhance in-vivo research. A modernised, dynamic framework is proposed comprising six inter-connected principles: replace, reduce, refine, re-engineer, revolutionise and re-imagine. Together, these 6Rs better reflect the contemporary scientific, technological and societal context of pre-clinical nuclear medicine. AI and digital methods augment the classical 3Rs, re-engineer research pipelines, generate measurable "12E" outcomes (enhanced, efficient, effective, ethical, environmental, economical, evidence-driven, equitable, evolutionary, empowered, enduring and elastic) and revolutionise translational capability. The 6R model provides a future-ready ethical and operational architecture for pre-clinical nuclear medicine, aligning radioligand development and mechanistic imaging research with modern principles of sustainability, transparency, computational innovation and animal welfare.