Molecular Imaging of In Vivo Zinc Distribution Using Nuclear and Magnetic Resonance Imaging

Zinc, a ubiquitous trace element, is essential to numerous biological processes, including enzymatic catalysis, gene expression, and cellular signaling. Precise zinc homeostasis, maintained by a complex interplay of transporters, storage proteins, and regulatory mechanisms, is critical for cellular function and organismal health. Disrupted zinc homeostasis has been implicated in the pathophysiology of diabetes, neurodegenerative disorders, and cancers, through alterations in zinc-dependent signaling pathways, oxidative stress responses, and apoptosis mechanisms. Thus, zinc biodistribution is a potential biomarker enabling improved detection of zinc-related pathologies, assessment of disease prognosis, and development of more targeted prevention strategies. While fluorescence techniques have advanced our understanding of cellular zinc, their application in human studies remains restricted. This highlights the need for zinc-specific biosensors that can be integrated with clinical imaging technologies, such as Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), and Magnetic Resonance Imaging (MRI), to enable in vivo visualization of zinc distribution and dynamics. This review describes the mechanistic understanding of zinc-associated diseases, details the design principles of molecular zinc biosensors (including radiopharmaceuticals and MRI contrast agents), and identifies the challenges and future directions for developing more specific and sensitive probes. For nuclear imaging (PET and SPECT), this includes probes utilizing radioactive zinc ions ⁶⁵Zn, ⁶²Zn, and ⁶³Zn, and zinc chelators labeled with isotopes like ¹⁸F, ¹¹C, and ¹²⁵I. For MRI, detection mechanisms leverage relaxivity (r ₁), Chemical Exchange Saturation Transfer (CEST), and hyperpolarization technologies. These imaging modalities exhibit the potential of bridging the gap between cellular and systemic zinc organ-level dynamics, offering a "horizontal" perspective on disease pathogenesis and facilitating precision medicine.