Reviews and CommentaryOpen Access

FAPI PET: Fibroblast Activation Protein Inhibitor Use in Oncologic and Nononcologic Disease

Published Online:https://doi.org/10.1148/radiol.220749

Abstract

Gallium 68 (68Ga)–labeled fibroblast activation protein (FAP) inhibitor (FAPI) PET is based on the molecular targeting of the FAP, which is known to be highly expressed in the major cell population in tumor stroma, termed cancer-associated fibroblasts. Among many FAP-targeted radiopharmaceuticals developed so far, 68Ga-FAPI exhibits rapid tracer accumulation in target lesions and low background signal, which results in excellent imaging features. FAPI PET can be integrated in the clinical workflow and enables the detection of small primary or metastatic lesions, especially in the brain, liver, pancreas, and gastrointestinal tract due to the low tracer accumulation in these organs. Moreover, the DOTA (1,4,7,10-tetraazacylclododecane-1,4,7,10-tetrayl tetraacetic acid) chelator in the molecular structure allows coupling of the FAPI molecules with therapeutic emitters such as yttrium 90 for theranostic applications. This review provides an overview of the state of the art in FAP imaging, summarizes the current knowledge of relevant cancer biology, and highlights the latest findings in the clinical use of 68Ga-FAPI PET and other current FAPI tracers.

Published under a CC BY 4.0 license

Summary

Gallium 68–labeled fibroblast activation protein inhibitor PET is an oncologic imaging strategy based on the molecular targeting of fibroblast activation protein highly expressed in the stroma of epithelial tumors.

Essentials

  • ■ Gallium 68 (68Ga)–labeled fibroblast activation protein (FAP) inhibitor (FAPI) for PET imaging is a radiotracer that can help detect small primary or metastatic lesions in crucial organs like the brain, liver, pancreas, and gastrointestinal tract.

  • 68Ga-FAPI PET is especially useful for tumors with a strong desmoplastic reaction, such as breast, colon, and pancreatic cancers, as well as peritoneal carcinomatosis, which show high lesion uptake with sharp image contrast.

  • ■ The most widely used 68Ga-labeled FAPIs (eg, 68Ga-FAPI-04, FAPI-74) and further developed FAP–targeting peptides are characterized by rapid and stable tracer accumulation in target lesions.

  • ■ DOTA chelator in the molecular structure allows coupling of the FAPI molecules with therapeutic emitters such as lutetium 177 and yttrium 90 for theranostic applications.

  • ■ Wound healing, fibrosis (liver, kidney, lung), and inflammation (eg, rheumatoid arthritis, Crohn disease, atherosclerosis, myocardial ischemia) can also be visualized using 68Ga-FAPI PET.

Introduction

Fibroblast activation protein (FAP) inhibitor (FAPI) used for PET imaging is a strategy that targets the cell population in the tumor surrounding stroma, termed cancer-associated fibroblasts. Though heterogeneous in origin, cancer-associated fibroblasts can be identified by the upregulation of several surface markers, of which the FAP, a membrane-bound type 2 serine protease belonging to the dipeptidyl peptidase 4 family, represents the most specific surface marker. There have been a few approaches to effectively target this molecule with radiolabeled ligands (eg, antibodies, peptides, or small molecule inhibitors). Among the FAP-based radiotracers developed so far, gallium 68 (68Ga)–labeled FAPIs provide the most favorable imaging features in terms of high detection rate in a variety of tumors, even in cases considered to be challenging for conventional fluorine 18 (18F) fluorodeoxyglucose (FDG) PET. Activation of fibroblasts occurs not only in the tumor surrounding tissue but also under benign conditions such as in wound healing, inflammation, or ischemia. Thus, FAPI PET imaging may also have potential to depict several common benign disease processes that are associated with widespread morbidity.

Background Biology: Activated Fibroblasts in Tumor Stroma

Tumor Stroma and/or Tumor Microenvironment in Oncology

In recent years, the tumor microenvironment has gained growing attention in the context of universal diagnostic and therapeutic strategies in oncology (1,2). Tumor stroma is reported to develop around malignant cells exceeding a size of 1–2 mm, which provides the basis for visualizing this phenomenon with FAP-targeting strategies (3). The tumor microenvironment is characterized by the abundance of cellular and noncellular components, including fibroblasts, vascular and immune cells, and the extracellular matrix. Increasing evidence suggests that the stroma is the site of a complex crosstalk between neoplastic and nonneoplastic cells, playing a crucial role in tumor development and growth. Multiple growth factors and angiogenic factors secreted from stromal cells, such as transforming growth factor β, vascular endothelial growth factor, interleukin 6, or tumor necrosis factor α lead to the upregulation of oncogenes as well as pro-oncogenic factors and enhance cancer metabolism (3). The tumor microenvironment appears not only to provide mechanical and nutritional support to the malignant cells but also to be fundamentally involved in tumor progression, invasion, metastasis, immunosurveillance, and drug resistance (2,3) (Fig 1).

Illustrations of tumor environment. (A) Neoplastic tissue and,                         therefore, the tumor microenvironment comprise a variety of components apart                         from cancer cells alone. When reaching a size of 2–3 mm, the                         tumor-associated stroma plays a crucial role in growth and progression, and                         it may even contribute up to 90% of the malignant mass. The tumor stroma                         mainly consists of the basement membrane, immune cells, vascular network,                         and cancer-associated fibroblasts. (B) Cancer-associated fibroblasts are                         responsible for vital processes of malignant tumors. Through different                         transmitters and pathways, cancer-associated fibroblasts enhance cell                         invasion and promotion of metastases. Simultaneously, they facilitate tumor                         growth, enable angiogenesis, and influence immune responses. Already these                         few features undermine the importance of cancer-associated fibroblasts                         regarding malignant tumors and their potential for diagnostic and                         therapeutic implications. (C) Gaussian surface (left) and fibroblast                         activation protein (FAP) receptor (right). The illustrations in the middle                         show the interaction of relevant amino acids within FAP receptor with its                         ligand linagliptin. FSP1 = fibroblast-specific protein, HGF1 = hepatocyte                         growth factor, IL6 = interleukin 6, MMP = matrix metalloproteases, PDGF =                         platelet-derived growth factor, TGF-β = transforming growth factor                         β, VEGF = vascular endothelial growth factor. Images were generated                         using data sets 1Z68 and 6Y0F from references 59 and 60.

Figure 1: Illustrations of tumor environment. (A) Neoplastic tissue and, therefore, the tumor microenvironment comprise a variety of components apart from cancer cells alone. When reaching a size of 2–3 mm, the tumor-associated stroma plays a crucial role in growth and progression, and it may even contribute up to 90% of the malignant mass. The tumor stroma mainly consists of the basement membrane, immune cells, vascular network, and cancer-associated fibroblasts. (B) Cancer-associated fibroblasts are responsible for vital processes of malignant tumors. Through different transmitters and pathways, cancer-associated fibroblasts enhance cell invasion and promotion of metastases. Simultaneously, they facilitate tumor growth, enable angiogenesis, and influence immune responses. Already these few features undermine the importance of cancer-associated fibroblasts regarding malignant tumors and their potential for diagnostic and therapeutic implications. (C) Gaussian surface (left) and fibroblast activation protein (FAP) receptor (right). The illustrations in the middle show the interaction of relevant amino acids within FAP receptor with its ligand linagliptin. FSP1 = fibroblast-specific protein, HGF1 = hepatocyte growth factor, IL6 = interleukin 6, MMP = matrix metalloproteases, PDGF = platelet-derived growth factor, TGF-β = transforming growth factor β, VEGF = vascular endothelial growth factor. Images were generated using data sets 1Z68 and 6Y0F from references 59 and 60.

Cancer-associated Fibroblasts as the Target Cell Population

Cancer-associated fibroblasts constitute the major subpopulation of cells in the tumor stroma (2,3). They are reactive fibroblasts, originating from a variety of benign cells including fibroblasts, adipocytes, endothelial cells, and others. The fibroblasts are activated via stimuli-like hypoxia or oxidative stress to release growth factors. In the course of activation, fibroblasts are transformed from spindle shape into stellate or cells, expressing several surface markers such as α-smooth muscle actin, platelet-derived growth factor β, or FAP, which seems to be the most specifically upregulated surface protein (3). Cancer-associated fibroblasts are found in numerous tumors, especially in cancers with strong desmoplastic reactions such as breast, colorectal, pancreatic, prostate, and lung cancer. Accordingly, FAP expression is found in more than 90% of epithelial tumors. As of now, the FAP expression is reported to be associated with a worse prognosis, as shown in colorectal, pancreatic, hepatocellular, and ovarian cancer (1). Although more studies are needed, this aspect makes cancer-associated fibroblasts an attractive target for antitumor therapy. In practical use, the low expression of FAP in quiescent fibroblasts or in healthy adult tissues is beneficial for selective imaging of pathologic changes with low background signal. To note, similar cellular activities occurring in the tumor microenvironment are also observed in wound healing or inflammatory tissue process, providing the basis for visualizing those nonmalignant conditions with the same imaging procedure.

Targeting FAP

The development of imaging techniques requires molecules with selective tracer binding and a rapid, high rate of radioligand uptake and fast clearance from circulation. Among the FAP tracers developed so far, 68Ga-FAPIs provide the most favorable features, mostly fulfilling the above-mentioned demands with increasing clinical evidence.

FAP Characteristics

FAP is a membrane-anchored glycoprotein consisting of 760 amino acids with a short intracellular (six amino acids), transcellular (20 amino acids), and a large extracellular (734 amino acids) domain (4). FAP belongs to the dipeptidyl peptidase family, the most familiar protein being dipeptidyl peptidase IV, also known as CD26, with which FAP shares up to 48% of the amino acid sequence. FAP characteristically possesses both postproline peptidase and endopeptidase activity, enabling FAP to cleave proteins in the surrounding tissue, thus promoting protein degradation and matrix remodeling.

FAPI Tracers

The main challenge to obtain therapeutic efficacy with clinical tolerability was notably overcome with tracers based on enzyme inhibition. Jansen et al (61) proposed several small enzyme inhibitors specific for FAP, including UAMC-1110 with increased specificity for FAP. Through the chemical modification of the quinoline group of UAMC-1110, resulting in the successful attachment of different chelators, Lindner et al (5) were the first to synthesize 68Ga-labeled FAPIs with specific binding to FAP, which presented a rapid and almost complete internalization of the ligand-receptor complex (Fig 2). Subsequent dosimetric analysis comparing 68Ga-FAPI-02 and -04 in patients revealed a favorable equivalent dose of approximately 3–4 mSv for 200 MBq of both radiopharmaceuticals, which is comparable to 18F-FDG or 68Ga DOTA-(Tyr3)-octreotate (DOTATATE) (6). Further improvement in tumor-to-background ratios (TBRs) with higher image contrast was achieved, especially for 68Ga-FAPI-21 and -46 (7). In particular, 68Ga-FAPI-46 showed an increasing TBR over time, making this tracer a promising tool for future theranostic applications.

Overview of advanced fibroblast activation protein (FAP) ligands. All                         depicted FAP ligands share a highly similar pharmacophore and/or FAP-binding                         domain. AlF-FAPI-74 is a pure diagnostic FAP inhibitor and can be labeled                         with fluorine 18 (or gallium 68 [68Ga]). The remaining FAP ligands are all                         capable of binding theranostic radionuclides like 68Ga, lutetium 177,                         yttrium 90, samarium 153, and actinium 225 via their DOTA                         (1,4,7,10-tetraazacylclododecane-1,4,7,10-tetrayl tetraacetic acid) or                         DOTAGA (DOTA-GA anhydride) chelator.

Figure 2: Overview of advanced fibroblast activation protein (FAP) ligands. All depicted FAP ligands share a highly similar pharmacophore and/or FAP-binding domain. AlF-FAPI-74 is a pure diagnostic FAP inhibitor and can be labeled with fluorine 18 (or gallium 68 [68Ga]). The remaining FAP ligands are all capable of binding theranostic radionuclides like 68Ga, lutetium 177, yttrium 90, samarium 153, and actinium 225 via their DOTA (1,4,7,10-tetraazacylclododecane-1,4,7,10-tetrayl tetraacetic acid) or DOTAGA (DOTA-GA anhydride) chelator.

Recent Approaches

Other recent approaches to target FAP are based on peptide or peptidomimetic compounds. OncoFAP (Philogen) is a small organic FAP ligand with ultrahigh affinity (8). [68Ga]Ga-OncoFAP DOTA-GA anhydride (DOTAGA) is reported to bind to human FAP in a subnanomolar concentration range, with rapid tracer accumulation and low immunogenicity due to its low molecular weight (9). The tracer accumulation profile of 10 minutes to 3 hours after administration is comparable to that of [68Ga]Ga-FAPI-04. Its clinical use after radiolabeling with therapeutic emitters will be the subject of future investigations.

Cancer Imaging with 68Ga-FAPI PET

FDG versus FAPI

Although 18F-FDG is currently the most widely used radiotracer for PET imaging in oncology, it has substantial disadvantages for a variety of applications. Nonspecific and physiologic radiotracer uptake in crucial organs reduces the diagnostic accuracy in many cases. FAPI PET is independent of glucose activity, leading to the drastic reduction of background signal in the brain, liver, oro- and nasopharyngeal mucosa, or gastrointestinal tract. In practical use, 68Ga-FAPI can be used without any dietary preparation and provides stable tracer uptake 10 minutes to 3 hours after administration. 18F-labeled FAP ligands such as FAPI-74 allow a larger batch production with lower costs (10). Considering the favorable organ distribution and high image quality, 18F-FAPI-74 possesses the potential to outperform FDG. Furthermore, phase 2 studies have been recently initiated—particularly in the field of oncologic PET imaging.

A broad overview of the larger studies reveals superior performance for FAPI PET, especially in the detection of primary or metastatic liver lesions and pancreatic, gastric, colon, lung, and ovarian cancers (1114) (Figs 3, 4). Peritoneal carcinomatosis is an entity increasingly mentioned in many studies for showing clear superiority over FDG, as in a targeted study encompassing 46 patients with peritoneal carcinomatosis (15). In different metastatic lesions, an overall high detection rate was found for lymph nodes, bone, lung, and visceral metastasis in larger studies, leading to changes in clinical staging (Fig 5). Although the documented intensity of the uptake value has varied for each tumor entity in subsequent studies, suspicious lesions are easily found because of the substantially low background signal, which leads to a high TBR with sharp image contrast (Fig 6).

Intraindividual comparison of fluorodeoxyglucose (FDG) versus                         fibroblast activation protein inhibitor (FAPI) PET in cancer. Images were                         obtained in six patients with six different tumor entities who underwent                         fluorine 18 (18F) FDG PET and gallium 68 (68Ga) FAPI PET within fewer than 9                         days. Five of the six patients show similar strong tumor uptake with 18F-FDG                         and 68Ga-FAPI, and three of six could benefit from a lower background signal                         in the liver or pharyngeal mucosa. In contrast, the patient with                         iodine-negative thyroid cancer showed only minor 68Ga-FAPI tracer uptake                         compared with 18F-FDG. Ca = cancer, NSCLC = non–small cell lung                         cancer. (Adapted, under a CC BY license, from reference 6.)

Figure 3: Intraindividual comparison of fluorodeoxyglucose (FDG) versus fibroblast activation protein inhibitor (FAPI) PET in cancer. Images were obtained in six patients with six different tumor entities who underwent fluorine 18 (18F) FDG PET and gallium 68 (68Ga) FAPI PET within fewer than 9 days. Five of the six patients show similar strong tumor uptake with 18F-FDG and 68Ga-FAPI, and three of six could benefit from a lower background signal in the liver or pharyngeal mucosa. In contrast, the patient with iodine-negative thyroid cancer showed only minor 68Ga-FAPI tracer uptake compared with 18F-FDG. Ca = cancer, NSCLC = non–small cell lung cancer. (Adapted, under a CC BY license, from reference 6.)

Fibroblast activation protein inhibitor (FAPI) versus                         fluorodeoxyglucose (FDG) PET in various cancer entities. Diagram shows                         comparison of FAPI and FDG PET in the diagnostic characteristic of various                         cancer entities based on the current studies (reference numbers are in                         brackets). BTC = biliary tract cancer, CCC = cholangiocellular carcinoma,                         HCC = hepatocellular carcinoma.

Figure 4: Fibroblast activation protein inhibitor (FAPI) versus fluorodeoxyglucose (FDG) PET in various cancer entities. Diagram shows comparison of FAPI and FDG PET in the diagnostic characteristic of various cancer entities based on the current studies (reference numbers are in brackets). BTC = biliary tract cancer, CCC = cholangiocellular carcinoma, HCC = hepatocellular carcinoma.

Fibroblast activation protein inhibitor (FAPI) PET/CT scans of various                         cancer entities. Maximum intensity projections in several patients                         undergoing FAPI PET/CT include a variety of different tumor entities. Ca =                         cancer, CCC = cholangiocellular carcinoma, CUP = cancer of unknown primary,                         MTC = medullary thyroid carcinoma, NET = neuroendocrine tumor. (Adapted,                         under a CC BY license, from reference 12.)

Figure 5: Fibroblast activation protein inhibitor (FAPI) PET/CT scans of various cancer entities. Maximum intensity projections in several patients undergoing FAPI PET/CT include a variety of different tumor entities. Ca = cancer, CCC = cholangiocellular carcinoma, CUP = cancer of unknown primary, MTC = medullary thyroid carcinoma, NET = neuroendocrine tumor. (Adapted, under a CC BY license, from reference 12.)

Image obtained in a 61-year-old man with newly diagnosed squamous cell                         carcinoma of the lung for initial tumor staging. (A) Maximum intensity                         projection of fluorine 18 (18F) fibroblast activation protein inhibitor                         (FAPI)-74 PET scan shows the wide distributions of tumor metastases.                         (B–F) CT scans (left) and axial fused FAPI PET/CT images (right). (C)                         Axial fused FAPI PET/CT scan enables favorable discrimination between tumor                         (arrows) and myocardium. (B, D) Some fibroblast activation                         protein–positive lesions (arrows) were confirmed with CT correlate                         (left images), whereas additional bone lesions (arrows) were only detected                         with FAPI PET (E, F, right image). All arrows represent FAPI uptake with                         morphologic correlation. (Adapted, under a CC BY license, from reference                         10.)

Figure 6: Image obtained in a 61-year-old man with newly diagnosed squamous cell carcinoma of the lung for initial tumor staging. (A) Maximum intensity projection of fluorine 18 (18F) fibroblast activation protein inhibitor (FAPI)-74 PET scan shows the wide distributions of tumor metastases. (B–F) CT scans (left) and axial fused FAPI PET/CT images (right). (C) Axial fused FAPI PET/CT scan enables favorable discrimination between tumor (arrows) and myocardium. (B, D) Some fibroblast activation protein–positive lesions (arrows) were confirmed with CT correlate (left images), whereas additional bone lesions (arrows) were only detected with FAPI PET (E, F, right image). All arrows represent FAPI uptake with morphologic correlation. (Adapted, under a CC BY license, from reference 10.)

Images in a 66-year-old man who had undergone radical gastrectomy for                         gastric adenocarcinoma and presented with abdominal pain and rising tumor                         marker levels. (A) Images from fluorine 18 (18F) fluorodeoxyglucose (FDG)                         PET/CT show the thickened pleura and multiple nodules in the peritoneum and                         mesentery, with low-to-moderate 18F-FDG activity in these lesions (left                         image: anterior maximum intensity projection image from 18F FDG PET; right                         images: axial fused PET/CT images). (B) Images from gallium 68 (68Ga)                         fibroblast activation protein inhibitor (FAPI) PET/CT show much higher                         tracer uptake in the thickened pleura (dashed arrow) and peritoneal nodules                         (solid arrows) (right image: anterior maximum intensity projection image                         from FAPI PET; left images: axial fused PET/CT images). Subsequent biopsy of                         pleura and peritoneal nodules revealed metastatic gastric adenocarcinoma                         (poorly differentiated). (Reprinted, under a CC BY license, from reference                         24.)

Figure 7: Images in a 66-year-old man who had undergone radical gastrectomy for gastric adenocarcinoma and presented with abdominal pain and rising tumor marker levels. (A) Images from fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT show the thickened pleura and multiple nodules in the peritoneum and mesentery, with low-to-moderate 18F-FDG activity in these lesions (left image: anterior maximum intensity projection image from 18F FDG PET; right images: axial fused PET/CT images). (B) Images from gallium 68 (68Ga) fibroblast activation protein inhibitor (FAPI) PET/CT show much higher tracer uptake in the thickened pleura (dashed arrow) and peritoneal nodules (solid arrows) (right image: anterior maximum intensity projection image from FAPI PET; left images: axial fused PET/CT images). Subsequent biopsy of pleura and peritoneal nodules revealed metastatic gastric adenocarcinoma (poorly differentiated). (Reprinted, under a CC BY license, from reference 24.)

Images obtained for primary staging in a 58-year-old man with                         pancreatic ductal adenocarcinoma. (A) Axial contrast-enhanced (ce) CT images                         of pancreatic ductal adenocarcinoma and liver in arterial (upper image) and                         venous (lower image) phase. (B) Mean intensity projection images from                         fluorine 18 (18F) fluorodeoxyglucose (FDG) (left) and gallium 68 (68Ga)                         fibroblast-activation protein inhibitor (FAPI) (right) PET/CT. (C) Axial                         fused 18F-FDG CT image (upper row, right image) and FAPI PET/CT image (lower                         row, right image) in the same patient at the level (blue line in B) of the                         pancreatic tumor mass and another suspicious FAPI accumulation in projection                         on perihepatic lymph node (corresponding CT scans, middle images). A                         metastatic situation, which had been revealed with FAPI PET/CT, was                         confirmed with biopsy of pulmonary lesion that was diagnosed as metastasis                         of known pancreatic ductal adenocarcinoma. (Adapted, under a CC BY license,                         from reference 53.)

Figure 8: Images obtained for primary staging in a 58-year-old man with pancreatic ductal adenocarcinoma. (A) Axial contrast-enhanced (ce) CT images of pancreatic ductal adenocarcinoma and liver in arterial (upper image) and venous (lower image) phase. (B) Mean intensity projection images from fluorine 18 (18F) fluorodeoxyglucose (FDG) (left) and gallium 68 (68Ga) fibroblast-activation protein inhibitor (FAPI) (right) PET/CT. (C) Axial fused 18F-FDG CT image (upper row, right image) and FAPI PET/CT image (lower row, right image) in the same patient at the level (blue line in B) of the pancreatic tumor mass and another suspicious FAPI accumulation in projection on perihepatic lymph node (corresponding CT scans, middle images). A metastatic situation, which had been revealed with FAPI PET/CT, was confirmed with biopsy of pulmonary lesion that was diagnosed as metastasis of known pancreatic ductal adenocarcinoma. (Adapted, under a CC BY license, from reference 53.)

Images in a 46-year-old man with newly diagnosed lung adenocarcinoma                         for tumor staging. (A) Fluorine 18 (18F)–labeled fluorodeoxyglucose                         (FDG) maximum intensity projection PET image, (B) axial fused 18F-FDG PET/CT                         image of lung, and (C, D) axial fused 18F-FDG PET/CT images of mediastinum                         and neck. (E) Gallium 68 (68Ga)–labeled fibroblast activation protein                         inhibitor (FAPI) maximum intensity projection image, (F) axial fused                         68Ga-FAPI PET/CT image of the lung, and (G, H) axial fused 68Ga-FAPI images                         of mediastinum and neck. Primary lung cancer (size, 4.9 × 4.2 cm) in                         the lower lobe of right lung was detected with intense uptake of 18F-FDG and                         68Ga-FAPI (maximum standardized uptake value, 10.4 and 12.4) (A, B, E, F).                         Multiple small lung metastases were also observed with both techniques (B,                         F). 18F-FDG PET/CT images show multiple positive lymph nodes in right hilum                         and mediastinum (A, C). 68Ga-FAPI PET/CT images depict more positive lymph                         nodes not only in right hilum and mediastinum (E, G) but also in the left                         lower neck (H, arrow), which is negative on 18F-FDG PET/CT image (D, arrow).                         Maximum intensity projection 68Ga-FAPI PET/CT image depicts four bone                         metastases in the thoracic spine, lumbar spine, and left iliac bone (E,                         arrows), whereas maximum intensity projection 18F-FDG PET/CT image only                         depicts two lesions in the thoracic and lumbar spine with much lower tracer                         uptake (A, arrows) (Reprinted, with permission, from reference                         27.)

Figure 9: Images in a 46-year-old man with newly diagnosed lung adenocarcinoma for tumor staging. (A) Fluorine 18 (18F)–labeled fluorodeoxyglucose (FDG) maximum intensity projection PET image, (B) axial fused 18F-FDG PET/CT image of lung, and (C, D) axial fused 18F-FDG PET/CT images of mediastinum and neck. (E) Gallium 68 (68Ga)–labeled fibroblast activation protein inhibitor (FAPI) maximum intensity projection image, (F) axial fused 68Ga-FAPI PET/CT image of the lung, and (G, H) axial fused 68Ga-FAPI images of mediastinum and neck. Primary lung cancer (size, 4.9 × 4.2 cm) in the lower lobe of right lung was detected with intense uptake of 18F-FDG and 68Ga-FAPI (maximum standardized uptake value, 10.4 and 12.4) (A, B, E, F). Multiple small lung metastases were also observed with both techniques (B, F). 18F-FDG PET/CT images show multiple positive lymph nodes in right hilum and mediastinum (A, C). 68Ga-FAPI PET/CT images depict more positive lymph nodes not only in right hilum and mediastinum (E, G) but also in the left lower neck (H, arrow), which is negative on 18F-FDG PET/CT image (D, arrow). Maximum intensity projection 68Ga-FAPI PET/CT image depicts four bone metastases in the thoracic spine, lumbar spine, and left iliac bone (E, arrows), whereas maximum intensity projection 18F-FDG PET/CT image only depicts two lesions in the thoracic and lumbar spine with much lower tracer uptake (A, arrows) (Reprinted, with permission, from reference 27.)

Images in a 63-year-old woman with metastasized ovarian carcinoma who                         underwent gallium 68 (68Ga)–labeled fibroblast activation protein                         inhibitor (FAPI) PET/CT (left images) followed by fluorine 18 (18F)                         fluorodeoxyglucose (FDG) PET/CT (right images) 1 month later. (A, E)                         Anterior maximum intensity projection images from 68Ga-FAPI PET (A) and                         18F-FDG PET (E). (B–D, F–H) Axial fused PET/CT images depict                         bone metastases in the upper thoracic spine (B, F; arrow) and the lower                         thoracic spine (D, H; arrow) and a liver metastasis in segment I (C, G;                         arrow) with a rather high FAPI uptake (left images) compared with FDG (right                         images) (maximum standardized uptake value [SUVmax] of FAPI vs FDG: 7.5 vs                         3.5, respectively, in the bone metastasis in the upper thoracic spine, 6.5                         vs 2.6 in the bone metastasis in the lower thoracic spine, and 15.7 vs 9.2                         in the liver metastasis). (Adapted, under a CC BY license, from reference                         13.)

Figure 10: Images in a 63-year-old woman with metastasized ovarian carcinoma who underwent gallium 68 (68Ga)–labeled fibroblast activation protein inhibitor (FAPI) PET/CT (left images) followed by fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT (right images) 1 month later. (A, E) Anterior maximum intensity projection images from 68Ga-FAPI PET (A) and 18F-FDG PET (E). (B–D, F–H) Axial fused PET/CT images depict bone metastases in the upper thoracic spine (B, F; arrow) and the lower thoracic spine (D, H; arrow) and a liver metastasis in segment I (C, G; arrow) with a rather high FAPI uptake (left images) compared with FDG (right images) (maximum standardized uptake value [SUVmax] of FAPI vs FDG: 7.5 vs 3.5, respectively, in the bone metastasis in the upper thoracic spine, 6.5 vs 2.6 in the bone metastasis in the lower thoracic spine, and 15.7 vs 9.2 in the liver metastasis). (Adapted, under a CC BY license, from reference 13.)

Organ- and Tumor-specific Studies: Cancers for which FAPI is Superior to FDG

Organ- and tumor-specific studies reveal more details, especially regarding diagnostic performance compared with other imaging modalities (Table 1).

Table 1: Organ- and Tumor-specific Studies with FAPI PET

Table 1:

Glioblastoma.—Röhrich et al (33) first found in 2019 the elevated FAPI uptake and TBR in isocitrate dehydrogenase (IDH)–wildtype glioblastomas (maximum standardized uptake value [SUVmax], 4.2; TBR, 22.4) and grade III or IV, but not in grade II, IDH-mutant gliomas (SUVmax, 0.4; TBR, 1.8). Based on this finding, the authors concluded that FAPI PET allows noninvasive distinction between low-grade IDH-mutant and high-grade gliomas. Windisch et al (34) investigated glioblastoma for radiation therapy planning. They found that FAPI PET for target volume delineation resulted in gross tumor volumes containing tumor not covered by MRI gross tumor volume.

Nasopharyngeal carcinoma.—For nasopharyngeal carcinomas, Qin et al (35) showed lower SUVmax of primary tumors in FAPI (13.9 ± 5.1) than in FDG (17.7 ± 6.8). The same authors found that FAPI PET improved the delineation of skull base and intracranial invasion.

Head and neck cancer.—Syed et al (36) demonstrated in 14 patients with head and neck cancer high FAPI avidity in primary tumors (SUVmax, 14.6 ± 4.4) without comparison to FDG. With regard to radiation therapy planning, the same study showed that contouring with FAPI resulted in significantly larger gross tumor volume with three- and fivefold increase in FAPI enhancement as compared with CT-based gross tumor volume. Head and neck cancers of unknown primary tumor were investigated by Gu et al (37) in patients without any findings at FDG PET. FAPI PET depicted the primary tumor in seven of 18 patients (39%). Moderate to intense FAPI uptake (mean SUVmax, 8.8) and TBR of 4.5 were found in primary tumors (37).

Prostate cancer.—Kessel et al (38) showed in a study including six patients with metastatic castration-resistant prostate cancer the variable FAPI uptake ranging from 5.7 to 27.8 (38). Thus, FAPI PET as well as FDG PET might be used as a complementary imaging modality to prostate-specific membrane antigen PET for prostate cancer, particularly in tumors with a higher Gleason score.

Organ- and Tumor-specific Studies: Cancer Entities without Superiority of FAPI over FDG

Lymphoma.—Jin et al (39) demonstrated in a study including 11 patients with Hodgkin lymphoma and 62 with non-Hodgkin lymphoma an overall SUVmax of 9.5 ± 4.6 for FAPI PET/CT, with no difference in nodal and extranodal lesions (P > .05).

Multiple myeloma.—Elboga et al (40) found no significant superiority of FAPI PET/CT over FDG PET/CT in a study including 14 patients with multiple myeloma.

Theranostic Applications

The initial theranostic application of FAP-based radiotracers was performed using yttrium 90 (90Y)Y-FAPI-04 as reported by Lindner et al (5). In that study, 2.9 GBq of the therapeutic radiotracer was applied in a patient with metastasized breast cancer with good tolerability, leading to a substantial reduction of pain medication (5). Further successful clinical application was reported for 90Y- and samarium 153–labeled FAPI-46 (4143). Although more evidence is needed, multiple results in preclinical and clinical settings (eg, with actinium 225–labeled FAPI-04) suggest a potential of FAP tracers for a future theranostic application (43). An overview of the major FAP tracers for diagnostic and theranostic use is given in Table 2.

Table 2: Overview of the Major FAP Ligands

Table 2:

Noncancer Imaging

“Wounds That Do Not Heal”

Matrix remodeling and tissue repair are typically seen in benign conditions such as wound healing. Dvorak originally referred to tumors in this context as “wounds that do not heal” (2). Activated fibroblasts are found in scar formation (eg, in ischemic tissues after myocardial infarction), chronic inflammatory and/or destructive processes (rheumatoid arthritis, Crohn disease, atherosclerotic plaque, immunoglobulin G4–related diseases), fibrosis (liver, kidney, lung), and benign tumors. These are conditions that clinicians must be aware of for the correct interpretation of the acquired image with FAP-targeting tracers. On the other hand, if properly used, FAP-targeting tracers provide the effective noninvasive diagnostic strategy for the aforementioned diseases.

Cardiac Imaging with FAP

In one preclinical study, the uptake of (68Ga)Ga-FAPI-04 in the injured myocardium peaked on day 6 after acute myocardial infarction (44). In addition, in a retrospective patient study, an intense FAPI uptake was observed in the infarct region (45). Interestingly, in that study, the corresponding cardiac MRI scan revealed that regions with positive FAPI uptake were slightly larger than the pathologic changes seen at cardiac MRI, indicating that the FAPI-positive areas might include the adjacent viable zone. Another finding relevant for clinical use is that the previous infarct area detected at cardiac MRI showed no tracer uptake at FAPI PET. This is presumably due to the substantial reduction of activated fibroblasts during scar maturation and provides a basis for the possible differentiation between fresh and matured ischemia.

Liver, Kidney, and Lung Fibrosis

In the kidney, a significant correlation of FAPI uptake with the deteriorated kidney function was recently shown and confirmed by another study (46). Idiopathic pulmonary fibrosis is more challenging to diagnose than kidney fibrosis due to the absence of suitable surface markers for disease monitoring. In a preclinical trial, FAPI PET showed a promising result with significantly higher tracer uptake in bleomycin-induced fibrotic lung of mice (47). Another recent report on [68Ga]Ga-FAPI-46–positive and 18F-FDG–negative findings in the lung after COVID-19 infection suggests the potential efficacy of FAPI PET in the evaluation of fibrous changes in the infectious or postinfectious lung (48). For liver fibrosis, elevated FAP expression in hepatic stellate cells was identified in the periseptal areas of the cirrhotic liver, indicating the efficacy of using FAPI PET for the assessment of active fibrosis (49).

Other FAP-positive Benign Conditions

In chronic inflammation, intestinal myofibroblasts play a key role in sustaining diseases, promoting fibroproliferative and stenotic changes. In Crohn disease, the elevated FAP expression was observed in areas with stricture (50). Interestingly, these changes were mostly absent in ulcerative colitis, providing the possibility for noninvasive differentiation of the two diseases.

Further FAP-positive findings with future potential for diagnostic use are immunoglobulin G4–related diseases, rheumatoid arthritis, atherosclerotic plaque, and checkpoint inhibitor–associated myocarditis.

Conclusion

Fibroblast activation protein inhibitor PET has diagnostic and therapeutic potential in oncology and even beyond. Future studies are needed for more evidence in each tumor entity, as well as the careful validation of nonmalignant conditions for the correct interpretation of the acquired images.

Disclosures of conflicts of interest: Y.M. No relevant relationships. K.D. No relevant relationships. J.C. No relevant relationships. C.K. Royalties from SOFIE Biosciences and iTheranostics; patents in the field of PSMA, FAP inhibitors; participates on advisory board on neuroendocrine tumors for Advanced Accelerator Applications Germany, a Novartis company; stock or stock options in FAPi-Holding. F.L.G. FAPI co-inventor; consulting fees from Telix Pharma, SOFIE, ABX, Alpha Fusion; royalties from iTheranostics and SOFIE Biosciences; patent for FAPI tracers licensed to SOFIE Biosciences. U.H. Royalties from iTheranostics and SOFIE Biosciences; patent for FAPI tracers licensed to SOFIE Biosciences.

Acknowledgments

We highly appreciate the support of Mike Reiss, Dipl Ing, for graphical design and illustration and Emil Novruzov, MD, for additional proofreading.

* F.L.G. and U.H. are co-senior authors.

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Article History

Received: Apr 14 2022
Revision requested: June 1 2022
Revision received: Aug 30 2022
Accepted: Sept 1 2022
Published online: Jan 03 2023