Fibroblast Activation Protein Inhibitor (FAPI)-Based Theranostics

Abstract

Fibroblast activation protein (FAP) is a serine protease selectively expressed in cancer-associated fibroblasts (CAFs), fibrotic tissues, and areas of active tissue remodeling, making it an attractive target for diagnostic imaging across a spectrum of disease. FAP inhibitors (FAPIs) labeled with PET tracers have rapidly advanced as a novel imaging modality with broad clinical applications that offers several advantages, including rapid tumor accumulation, low background uptake, and high tumor-to-background ratios. In oncology, FAPI PET has demonstrated excellent performance in visualizing a wide range of malignancies, including those with low glycolytic activity, such as pancreatic cancer, cholangiocarcinoma, and certain sarcomas. Its high sensitivity and specificity for the stromal component enables improved tumor delineation, staging, and response assessment. Additionally, the potential to guide theranostic approaches, where the same tracer can be labeled with therapeutic radionuclides, positions FAPI as a key player in precision oncology. Beyond oncology, FAPI PET has shown promise in imaging conditions characterized by fibrotic and inflammatory processes. In the cardiovascular field, FAPI PET imaging is being investigated for its ability to detect myocardial fibrosis and active cardiac remodeling, crucial in conditions like heart failure, post-myocardial infarction remodeling, and hypertrophic cardiomyopathy. This review highlights the expanding clinical applications of FAPI-based PET imaging across oncology, inflammation, and cardiovascular disease. While the current data are promising, further large-scale studies and multicenter trials are essential to validate these findings and establish standardized protocols. The versatility and broad applicability of FAPI PET underscore its potential as a transformative tool in precision medicine.

Keywords: FAPI; PET; theranostics.

Figure 1

The Tumor Microenvironment (TME): cancer-associated fibroblasts express fibroblast activation protein (FAP), which serves as a versatile target for PET imaging and therapeutic approaches with FAP inhibitors (image created in BioRender).

Figure 2

⁶⁸Ga-FAPI-46 PET/CT images of a 19-year-old female with metastatic papillary thyroid cancer (follicular variant). In addition to the cervical and lymph node metastases, false positive uptake is seen in the gallbladder on ⁶⁸Ga-FAPI-46.

Figure 3

⁶⁸Ga-FAPI-46 (top panel) and ¹⁸F-FDG PET/CT (bottom panel) images of a 60-year-old female with luminal A breast cancer (ER + ve, PR + ve, Ki-67 60%), demonstrating superior detection of visceral metastasis with FAPI compared to FDG. ⁶⁸Ga-FAPI (top panel) shows multiple foci of intense tracer accumulation in the liver, multiple ribs, vertebrae, and pelvis. Corresponding ¹⁸F-FDG images (bottom panel) show less intense and fewer areas of tracer accumulation compared to ⁶⁸Ga-FAPI.

Figure 4

65-year-old female with SCC of the distal esophagus; ⁶⁸Ga-FAPI-46 PET/CT demonstrates intense tracer accumulation in an extensive lesion extending from T2–T10 with no distant metastasis.

Figure 5

65-year-old female with renal cell carcinoma post right nephrectomy who presented with a mass in the region of the head of pancreas. ⁶⁸Ga-FAPI-46 (upper panel) shows avidity in the head of pancreas mass, right hilar lymph node, and the lung compared to ¹⁸F-FDG (lower panel). These lesions are better seen on the FAPI-46 PET images due to the better tumor-to-background ratio.