Radiolabelled Antisense miRNA Oligonucleotides for Molecular Imaging and Therapeutic Applications

Background/Objectives: MicroRNAs (miRNAs) are small non-coding RNAs (20–24 nucleotides) that regulate post-transcriptional gene expression and are involved in key biological processes, including proliferation and apoptosis. Dysregulation of miRNA expression is associated with numerous diseases, particularly cancer, making them attractive biomarkers and therapeutic targets for precision medicine. Antisense miRNA oligonucleotides (AMOs) have emerged as promising agents for selectively inhibiting miRNA activity. This review examines the development of radiolabelled AMOs targeting miRNAs for diagnostic and imaging applications, with particular attention to their radiolabelling, biological performance, delivery strategies, and potential therapeutic extension. Methods: The literature was examined with a focus on studies describing the synthesis of radiolabelled AMOs targeting miRNAs. Other oligonucleotide-based molecules, such as antisense oligonucleotides (ASOs) and peptide nucleic acids (PNAs), were not considered. Results: Current evidence demonstrates that AMOs can be efficiently radiolabelled with clinically relevant radionuclides, including 99mTc and 68Ga, using bifunctional chelating agents (BFCA) such as MAG3, DOTA, and NOTA while preserving their biological properties. These probes enable noninvasive imaging of their in vivo localization in regions of interest, supporting their potential for precision diagnostics. However, available studies remain limited, and significant challenges persist, particularly regarding targeted delivery, pharmacokinetics, and nonspecific uptake in excretory organs. Therapeutic applications remain at an early preclinical stage, with radioiodinated AMO-21 providing preliminary evidence for therapeutic use. Conclusions: Radiolabelled AMOs represent a potential approach for miRNA targeted molecular imaging, but their clinical translation remains challenging. Future studies should integrate optimized chemical modifications and delivery systems with rigorous in vivo validation and appropriate controls.