FAP and FAPI-PET/CT in Malignant and Non-Malignant Diseases: A Perfect Symbiosis?

Abstract

A fibroblast activation protein (FAP) is an atypical type II transmembrane serine protease with both endopeptidase and post-proline dipeptidyl peptidase activity. FAP is overexpressed in cancer-associated fibroblasts (CAFs), which are found in most epithelial tumors. CAFs have been implicated in promoting tumor cell invasion, angiogenesis and growth and their presence correlates with a poor prognosis. However, FAP can generally be found during the remodeling of the extracellular matrix and therefore can be detected in wound healing and benign diseases. For instance, chronic inflammation, arthritis, fibrosis and ischemic heart tissue after a myocardial infarction are FAP-positive diseases. Therefore, quinoline-based FAP inhibitors (FAPIs) bind with a high affinity not only to tumors but also to a variety of benign pathologic processes. When these inhibitors are radiolabeled with positron emitting radioisotopes, they provide new diagnostic and prognostic tools as well as insights into the role of the microenvironment in a disease. In this respect, they deliver additional information beyond what is afforded by conventional FDG PET scans that typically report on glucose uptake. Thus, FAP ligands are considered to be highly promising novel tracers that offer a new diagnostic and theranostic potential in a variety of diseases.

Head-to-head evaluation of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT in recurrent soft tissue sarcoma

“…It should be noted that the intensive uptake of [ 68 Ga]Ga-DOTA-FAPI-04 presenting in wound healing, uterus, arthritis, and periodontitis may be misdiagnosed as local relapse or distant metastasis. This is caused by fibrotic activity in these conditions [ 26 ]. Thus, more researches focused on non-tumor–specific uptake of FAPI are still needed [ 27 , 28 ].…”

Emerging Role of FAPI PET Imaging for the Assessment of Benign Bone and Joint Diseases

“…In this setting, fibroblast activation protein (FAP) inhibitors (FAPI), labelled with both 18 F or 68 Ga, are emerging as promising radiopharmaceuticals. FAPI are molecules able to bind to FAP, a membrane serine protease that is highly expressed on activated fibroblasts present in a wide range of pathophysiological conditions, such as wound-healing, inflammation and cancer [ 10 , 11 , 12 ]. In this scenario, the role of FAPI PET/CT for the evaluation of cancer has been evaluated in several studies and the preliminary results are promising, as it also seems to allow the evaluation of tumors with low [ 18 F]FDG uptake.…”

“…In this scenario, the role of FAPI PET/CT for the evaluation of cancer has been evaluated in several studies and the preliminary results are promising, as it also seems to allow the evaluation of tumors with low [ 18 F]FDG uptake. Interestingly, when coupled together, [ 18 F]FDG and radiolabeled FAPI are able to better define and comprehend tumoral metabolic heterogeneity [ 10 , 13 , 14 , 15 , 16 ].…”

“…The role of FAPI imaging is, however, also emerging for the assessment of inflammatory and infectious diseases, even if the evidence in the literature is still in its early stages [ 10 , 17 , 18 ]. It has been reported that focal radiolabeled FAPI uptake is related to active tissue remodeling in patients with immune-mediated inflammatory diseases that are characterized by the presence of chronic inflammation and tissue response.…”

“…The rationale behind the use of FAPI PET/CT for the assessment of inflammatory bone and joint diseases is that FAP is overexpressed in tissue remodeling sites associated with arthritis and fibrosis, such as chondrocytes [ 10 , 11 ]. However, on the other side, some authors hypothesized a different mechanism of uptake, related to the increased vascularity and capillary permeability due to inflammatory response, resulting in high perfusion and blood-pool effects [ 20 ].…”