Molecular imaging tracers targeting c-MET: a systematic review of preclinical evidence and clinical translation.

INTRODUCTION: The mesenchymal-epithelial transition factor (c-MET) is an emerging target for molecular imaging owing to its widespread overexpression across multiple cancer types. This systematic review evaluated radioactive and fluorescent c-MET-targeting tracers in preclinical and clinical studies, focussing on their translational potential and imaging performance. METHODS: This systematic review was conducted according to PRISMA 2020 guidelines. A PubMed, Embase, and Scopus search for studies evaluating radioactive or fluorescent c-MET-targeting tracers was complemented with expert-suggested reports. Tracer characteristics, imaging performance, and safety data were extracted. RESULTS: Fifty preclinical and thirteen clinical reports were included, comprising 62 distinct c-MET-targeting tracers across several compound classes. Only four peptide-based tracers progressed to clinical evaluation: the fluorescent tracers EMI-137 and cMBP-ICG, and the PET tracers ⁶⁸Ga-EMP-100 and ⁶⁸Ga-MetP. EMI-137 (8 studies) enabled fluorescence-guided tumour visualisation (tumour-to-background ratios; TBRs 1.3-9.7) and identified additional malignant lesions in selected applications. Although tracer uptake generally corresponded with c-MET expression, diagnostic performance was limited by uptake in benign c-MET-expressing tissues, yielding a sample-size weighted average sensitivity and specificity of 81.7% and 39.3%. cMBP-ICG (2 studies), evaluated exclusively in oral cavity cancer, demonstrated improved discrimination between malignant and benign tissue and outperformed conventional assessment for biopsy-site selection, reporting TBRs of 2.7-4.1 and a weighted average sensitivity and specificity of 85.5% and 91.1%. The PET tracers ⁶⁸Ga-EMP-100 (2 studies) and ⁶⁸Ga-MetP (1 study) demonstrated feasibility for whole-body c-MET PET imaging, with the latter additionally showing a positive correlation between tumour uptake and immunohistochemical c-MET expression. All four tracers showed favourable safety, with only mild adverse events reported. CONCLUSIONTARGETING TRACER PIPELINE. NUMBERS REPRESENT DISTINCT: Despite extensive preclinical development, only four peptide-based tracers have progressed to clinical evaluation. Clinical evidence supports the feasibility of c-MET-targeted molecular imaging but remains limited by methodological heterogeneity, small sample sizes, limited biological validation, and variable diagnostic performance. Larger, standardised studies are needed to establish the added clinical value and broader applicability of c-MET-targeting tracers in molecular imaging.