The biology behind the excitement is genuine. c-MET, the mesenchymal-epithelial transition factor, is a receptor that becomes activated when hepatocyte growth factor binds its extracellular domain, triggering a cascade of downstream signalling through partners such as Gab1, PI3K, MAPK and STAT3. This signalling drives cell motility, proliferation and survival, the hallmarks of invasive growth. In healthy tissue, c-MET expression is low and restricted mainly to epithelial and endothelial cells involved in repair and development. In cancer, however, the pathway is frequently dysregulated, producing receptor overexpression that is tightly linked to metastasis, therapy resistance and poorer survival across multiple tumour types. Reported overexpression reaches 26 to 82 percent in oral cavity squamous cell carcinoma, up to 87 percent in penile cancer, 15 to 67 percent in colorectal cancer, 17 to 81 percent in non-small cell lung cancer, 56 to 80 percent in renal cell carcinoma and 14 to 54 percent in breast cancer.

Critically for imaging, tumour tissue can show c-MET levels up to eleven times higher than surrounding epithelium, with a median ratio of 3.4. Imaging scientists generally consider a target diagnostically useful when it can be detected with a signal-to-background ratio above 1.5 to 2, placing c-MET squarely within the range worth pursuing. The review team conducted their search of PubMed, Embase and Scopus according to PRISMA 2020 guidelines, with the protocol registered on PROSPERO, and ultimately included 63 eligible reports: 50 preclinical animal studies published between 2002 and 2026 and 13 clinical reports from 2015 to 2026. The preclinical literature described 62 unique tracers, of which 44 carried a radioactive label and 18 a fluorescent one, distributed across three broad compound classes: monoclonal antibodies, peptides and small molecules.

Each scaffold carries its own pharmacokinetic personality. Monoclonal antibodies, at roughly 150 kilodaltons, showed the highest binding affinities and, in selected studies, the highest tumour-to-background ratios, but their slow circulation meant tumour uptake peaked three to four days after injection, forcing reliance on long-lived radionuclides such as zirconium-89, used in nearly 62 percent of antibody designs. Radiolabelled antibodies achieved tumour accumulation of 3 to 47 percent of injected dose per gram, with reported tumour-to-background ratios ranging from a dismal 0.1 to an impressive 43. Onartuzumab-based designs dominated this category, accounting for 38 percent of antibody tracers. Fluorescent antibody variants conjugated to IRDye800CW delivered comparable affinities of 1.0 to 1.3 nanomolar and tumour-to-background ratios near 5, peaking four days after injection.

Peptides, by contrast, occupy a pharmacokinetic sweet spot. Weighing between 0.5 and 5 kilodaltons, they combine rapid tumour targeting with fast systemic clearance, producing high contrast within hours and permitting short-lived isotopes such as technetium-99m and fluorine-18. Sixteen radiolabelled peptide tracers were identified, dominated by cMBP-derived designs, with binding affinities spanning 0.9 to 326 nanomolar and the best variants, such as the macrocyclic HiP-8, approaching antibody-like binding at around 1 nanomolar. Tumour uptake generally peaked within one to two hours, with reported tumour accumulation of 0.7 to 9.4 percent of injected dose per gram and tumour-to-background ratios of 1.7 to 20. Fluorescent peptide tracers followed a similar pattern, with Cy5-analogues the most popular fluorophores and reported ratios reaching as high as 33. Small molecules, though fast and capable of crossing cell membranes, showed generally lower tumour accumulation and contrast, with ratios of just 0.2 to 3.3, and remain the least mature class.

Yet when the authors traced which designs actually reached the clinic, the pattern was unambiguous: all four translated tracers were peptides. EMI-137, a macrocyclic 26-amino-acid peptide engineered with intramolecular cyclisation for subnanomolar-range affinity and renal clearance, was the most extensively studied, evaluated across eight clinical reports involving 102 participants in five tumour types. cMBP-ICG, a minimalist 12-amino-acid linear peptide conjugated to indocyanine green, was tested in 60 patients with oral cavity cancer. The PET tracers gallium-68-EMP-100 and gallium-68-MetP together accounted for three reports and 25 participants. The reasons others stalled remain unclear, but the authors point to a combination of affinity, stability, manufacturability, regulatory feasibility and the clinical relevance of the animal models used, factors that tracer performance metrics alone cannot predict.

The clinical data reveal both promise and frustration. EMI-137 enabled fluorescence-guided tumour visualisation with tumour-to-background ratios of 1.3 to 9.7, and in its landmark colorectal application, second-pass fluorescence endoscopy identified nine additional adenomatous lesions, roughly 19 percent, that white-light colonoscopy had missed. In papillary thyroid cancer, fluorescence reclassified disease from unifocal to multifocal in four of five patients by detecting foci as small as 1.4 millimetres invisible on preoperative ultrasound. But specificity suffered badly: benign c-MET-expressing tissues lit up too, yielding a sample-size weighted average sensitivity of 81.7 percent but a specificity of just 39.3 percent across EMI-137 studies. In laparoscopic colorectal surgery, fluorescence discriminated only 4 of 9 primary tumours and detected no nodal metastases despite histological confirmation in over half the patients.

The standout performer was cMBP-ICG, applied topically in oral cavity squamous cell carcinoma. Because the tracer was rinsed into the mouth rather than injected, systemic exposure was minimal and imaging immediate. A randomised controlled trial of 50 patients compared fluorescence-guided biopsy-site selection against conventional white-light inspection in the same patients, and fluorescence won decisively on every metric: sensitivity of 88 versus 65 percent, specificity of 93 versus 76 percent, positive predictive value of 90 versus 68 percent, negative predictive value of 91 versus 74 percent, and overall diagnostic accuracy of 91 versus 72 percent, with statistical significance across the board. Weighted averages across both cMBP-ICG studies showed 85.5 percent sensitivity and 91.1 percent specificity, with tumour-to-background ratios of 2.7 to 4.1. The two PET tracers demonstrated feasible whole-body c-MET imaging, and gallium-68-MetP produced the first clinical evidence of a quantitative correlation between tracer uptake and immunohistochemical c-MET expression, with a correlation coefficient of 0.71. All four tracers showed favourable safety, with only mild adverse events reported.

The review’s authors are candid about the caveats. Risk-of-bias assessment using the ROBINS-I tool judged the clinical evidence to carry serious methodological limitations, stemming from small sample sizes, absent control groups, unblinded outcome assessment and the predominance of single-arm early-phase feasibility studies. Preclinical work leaned heavily on a handful of high c-MET-expressing cell lines in subcutaneous xenografts, models that poorly recapitulate the heterogeneous expression and microenvironmental complexity of real tumours. Only one radiolabelled tracer report and seven fluorescent tracer reports used orthotopic models. Heterogeneity in study designs, outcome definitions and reporting was so great that a formal meta-analysis proved impossible, forcing the team into narrative synthesis with weighted averages that they themselves caution should be interpreted cautiously.

What emerges is a field at an inflection point. The biological rationale for c-MET imaging is solid, the safety profile of the leading tracers is reassuring, and the single randomised trial in oral cancer demonstrates that molecular imaging can genuinely outperform conventional assessment. The path forward, the authors argue, lies in larger, standardised prospective studies designed to prove that c-MET-targeted imaging improves clinically meaningful endpoints: lesion detection, staging accuracy, treatment selection and surgical decision-making. They also point toward synergy with therapy, noting that c-MET status already guides first-line treatment with MET tyrosine kinase inhibitors and antibody-drug conjugates in non-small cell lung cancer, raising the prospect of matched imaging and therapeutic agents in a theranostic paradigm. Until such evidence arrives, the 62-tracer graveyard of preclinical promise stands as a warning that in molecular imaging, a beautiful animal study is only the beginning of a very long road.

Subject of Research: Systematic review of preclinical and clinical molecular imaging tracers targeting the c-MET receptor in cancer

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

Article References: Verdijk, R. W. A., van der Mierde, S. M., Berehova, N., van Meerbeek, M. P., Brouwer, O. R., van der Poel, H. G., van Leeuwen, F. W. B., & Buckle, T. (2026). Molecular imaging tracers targeting c-MET: a systematic review of preclinical evidence and clinical translation. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08174-w

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08174-w

Keywords: c-MET, molecular imaging, fluorescence-guided surgery, PET imaging, EMI-137, cMBP-ICG, clinical translation, systematic review, tumour tracers, image-guided surgery, receptor tyrosine kinase, cancer diagnostics