From PET to targeted radionuclide therapy in the Brain: The emerging role of radiometal-based platforms.

Radiometal-based radiopharmaceuticals have become central to the advancement of molecular imaging and targeted radionuclide therapy, offering powerful tools for the diagnosis and treatment of diseases affecting the brain. The unique chemical versatility of radiometals - encompassing a broad range of coordination chemistries, physical half-lives, and emission properties - combined with an expanding repertoire of targeting biomolecules enables highly tunable and increasingly modular imaging and therapeutic platforms. In particular, positron emission tomography (PET) using radiometal-labelled tracers provides sensitive, quantitative, and non-invasive assessment of molecular processes in vivo, while radiometal-based therapeutic agents enable the selective delivery of cytotoxic radiation to diseased tissue. This review examines recent progress in the application of radiometal-based radiopharmaceuticals for brain disorders, with a focus on neuro-oncology - including primary brain tumours and brain metastases - as well as neurodegenerative diseases such as Alzheimer's disease and Parkinsons disease. Key challenges unique to brain applications are discussed, including the restrictive nature of the blood-brain barrier, heterogeneous target expression, and off-target biodistribution. Recent advances in chelator development, emerging antigen targets, alternative routes of administration, and strategies to improve brain delivery are highlighted. While imaging agents continue to lead therapeutic development in this space, reflecting the need for accurate disease characterisation, recent progress underscores the potential of radiometal-based therapies for brain disease. In particular, immunoPET has emerged as a powerful tool for evaluating target expression, biodistribution, and treatment response. Collectively, these developments position radiometal-based radiopharmaceuticals as a promising and evolving platform enabling personalised treatment strategies for neurological disorders.