Manganese-Enhanced Magnetic Resonance Imaging: From Translational Research to First-in-Human Trials in Oncology

Manganese-enhanced magnetic resonance imaging (MEMRI) is a functional imaging technique with several potential applications in various research fields. Manganese-enhanced magnetic resonance imaging uses paramagnetic manganese (II) ions (Mn²⁺) as the contrast enhancer, as they accumulate mainly in the cytosol and mitochondria, shorten the longitudinal relaxation time (T₁) and thereby increase signal intensity on T₁-weighted sequences. Most often used in preclinical neuroimaging, MEMRI is also gaining attention in cancer research, providing potentially new insights into tumour biology and treatment response monitoring. The use of MEMRI faces challenges such as the potential toxicity of free manganese and the need for chelation (mangafodipir trisodium, MnPyC3A), careful dosing below ≈25 µmol Mn²⁺/kg and development of new imaging protocols. Ongoing translational research aims to improve the safety profile of manganese agents and optimise imaging strategies. Early clinical studies in neurology and cardiology are exploring MEMRI; clinical oncology use remains investigational and limited. We review preclinical advances and the limited early human experience, outlining safety considerations and the potential, yet unproven, effectiveness of MEMRI in oncology. The present review also contextualises MEMRI within the broader landscape of metal-based precision imaging and neutron capture therapy approaches, including boron neutron capture therapy and gadolinium neutron capture therapy, which represent complementary strategies exploiting the tumour-selective accumulation of specific metal ions. Recent clinical and translational evidence supports the maturation of these approaches: a phase II trial of accelerator-based boron neutron capture therapy with borofalan in head and neck cancer reported acceptable safety, and a systematic review across malignant tumours confirmed favourable efficacy and safety signals for boron neutron capture therapy. Manganese-based nanotheranostics are concurrently emerging as a route to combine magnetic resonance imaging with image-guided therapy.