Nuclear Medicine
CLINICAL DECISION SUPPORT
[68Ga]Ga-FAPI
[18F]F-FAPI
[99mTc]Tc-FAPI
Tumours are cell assemblies consisting not only of malignant cells, but also of stroma cells which include vascular cells, inflammatory cells and fibroblasts. The stroma may represent more than 90% of the tumour mass in tumours with desmoplastic reaction such as breast, colon and pancreatic carcinoma. A stromal subpopulation of fibroblasts called cancer-associated fibroblasts (CAFs) is known to be involved in growth, migration and progression of tumours [322]. CAFs originate from different cells such as local fibroblasts, circulating fibroblasts, vascular endothelial cells via endothelial to mesenchymal transition, adipocytes, bone marrow derived stem cells or even from cancer cells via endothelial to mesenchymal transition which results in a heterogeneous proteome leading to differences in function. The activation of these cells leads not only to changes in morphology but also to the support of tumour cells for migration, proliferation, the production of a permissive extracellular matrix, and the expression of different markers such as smooth muscle actin (SMA), platelet derived growth factor (PDGFR ) and fibroblast activation protein (FAP). Activated fibroblasts occur not only in tumours, but also as a physiological phenomenon in healing wounds as well as in diseases with matrix remodelling such as chronic inflammation, rheumatoid diseases, heart infarction and liver and lung fibrosis [323].
There is at least one marker which is overexpressed in the stroma of many tumour entities and which can be used for imaging and/or therapy: the fibroblast activation protein (FAP) [324]. FAP is a type II membrane bound glycoprotein which belongs to the dipeptidyl peptidase 4 (DPP4) family. In contrast to DPP4, having only exopeptidase activity, FAP shows both, dipeptidyl peptidase and endopeptidase activity. Known physiological substrates for the endopeptidase activity are gelatin, denatured type I collagen, -antitrypsin and several neuropeptides such as neuropeptide Y, peptide YY, B-type natriuretic peptide and substance P. The enzyme is known to have a role in normal developmental processes during the embryogenesis and in tissue modelling. However, its expression in adult normal tissues usually does not exist or is very low. Examples of physiological FAP expression are the uterus, the cervix, the placenta, the breast and the skin, which show a low to moderate expression as compared to tumours. In contrast, a high expression occurs in wound healing, chronic inflammation such as rheumatoid diseases, chronic arthritis, artherosclerotic plaques and fibrosis. Since ischemic heart tissue after myocardial infarction induces matrix remodelling FAP can also be found in cardiac diseases. High expression is also seen in more than 90% of epithelial carcinomas. Since FAP is a membrane-anchored enzyme with its catalytic domain located at the extracellular part of the protein it can be addressed using small molecule inhibitors [325]. Therefore, known FAP inhibitors (FAPIs) have been modified to radiolabelled FAPIs [326–328]. After binding of FAPIs to FAP the tracers are rapidly internalized in FAP-presenting cells. In addition these molecules are very rapidly eliminated from the circulation leading to a high contrast even at early periods after tracer administration [326–328]. Furthermore, since tumour lesions exceeding a size of 1 to 2 mm require the formation of a supporting stroma, a visualization of small lesions in the range of 3-5 mm should be possible using these molecules.
FAPIs may be applied in all diseases showing extracellular remodelling. As mentioned above these are more than 90% of epithelial tumours, some sarcomas, but also non-malignant disease such as rheumatoid diseases, arthritis, artherosclerotic plaques, fibrosis and ischemic heart tissue after myocardial infarction. Possible indications are staging, restaging and therapy monitoring. Furthermore, due to the high contrast, the tracers may be useful for the planning of radiation therapy [329].
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At present, FAPIs are still in an experimental state. The publications so far are mainly concerned with oncological patients, but first results have been also reported in patients with heart diseases and rheumatoid diseases.
Oncology: A quantitative analysis of tracer uptake was performed in 80 patients with 28 different tumour entities. The highest average SUVmax (>12) was found in sarcomas, oesophageal, breast, cholangiocarcinoma and lung cancer, the lowest uptake (average SUVmax <6) was observed in pheochromocytoma, renal cell, differentiated thyroid, adenoid-cystic and gastric cancer and an intermediate SUVmax (SUV 6-12) was seen in patients with hepatocellular cancer, colorectal cancer, head-neck tumours, ovarian cancer, pancreatic cancer and prostate cancer. However, it has to be noted that the SUVs varied substantially across and within all tumour entities investigated in that analysis. Due to a rapid clearance from the circulation resulting in a very low background in muscle and blood-pool a high-contrast is obtained for PET imaging [330,331]. In contrast to [18F]FDG, which shows a high uptake in cells with a high need for glucose such as inflammatory tissue or the brain, FAPIs get only enriched in tissues where FAP-expressing fibroblasts occur. The fact that there is no or a very low FAPI uptake in all normal organs, especially the brain and the liver, opens new possibilities for the detection of malignant lesions in these regions based on the high contrast images obtained with that compound [326,330]. Furthermore, due to the rapid clearance only minimal changes in background were observed between 10 min and 3 h p.i.. Therefore, visualization of metastases with high contrast was obtained even at 10 minutes after tracer administration which may be used for early imaging allowing a higher number of patients in clinical routine.
In patients with gliomas IDH-wildtype glioblastomas and grade III/IV, but not grade II IDH-mutant gliomas showed increased FAPI uptake. This may allow non-invasive distinction between low-grade IDH-mutant and high-grade gliomas [332].
A comparison between FAPIs and [18F]FDG in 6 patients revealed that the tumour uptake was equal (average SUVmax 7.4 for both tracers). However, the background uptake in brain (11.01 vs 0.32), liver (2.77 vs 1.69) and oral/pharyngeal mucosa (4.88 vs 2.57) was significantly lower for FAPI-PET [330]. This seems to be a promising feature of the FAPI tracers with respect to the detection of brain or liver metastases, liver tumours or head-and-neck tumours. As expected, accumulation of FAPIs was observed not only in tumours, but also at sites with tissue remodelling such as chronic inflammation after vaccination, activated arthrosis and physiologically in the uterus [323].
Furthermore, since tracer clearance occurs via the kidneys without being retained in the renal parenchyma there seems to also a possible therapeutic application, especially in the setting of a combination therapy with chemotherapy or immunotherapy. This makes sense in the light of the fact that FAP-positive fibroblasts support chemo- and immunoresistance of tumours. However, due to the relatively short retention time in the tumour as compared to DOTATOC or PSMA ligands radionuclides with shorter half-lives are preferable than those with a longer half-life. This would be in favour of 188Re, 153Sm, 213Bi or 212Pb. However, therapy with 225Ac]Ac-FAPI-04 of PANC-1 tumour bearing mice showed a significant tumour growth suppression compared to controls, without a significant change in body weight [333]. A further promising aspect of a therapeutic application is the combination with radiation therapy by increasing the local dose or enabling a reduction of the externally delivered radiation leading to a decrease in side effects.
Cardiology: As mentioned above fibroblast may be activated also in non-malignant diseases such as injured myocardium after myocardial infarction. Therefore, FAPI-04 has been used in a rat model of myocardial infarction. Tracer uptake peaked in the infarct lesion at 6 days after ligation of the coronary artery which could be confirmed by immunofluorescence using anti-FAP antibodies [334]. Therefore, it is conceivable that FAPI-PET may have a diagnostic and prognostic value in the setting of the management of patients with myocardial infarction by quantifying the extracellular remodelling. Further indications may be cardiomyopathy caused by chemotherapy of cancer patients.
The suggested activities are:
[68Ga]Ga-FAPI: 200-300 MBq
[18F]F-FAPI: 200-300 MBq
[99mTc]Tc-FAPI: 500 MBq
However, changes are possible due to the still experimental character of the radiopharmaceuticals.
[68Ga]Ga-FAPIs: FAPI-02 and FAPI-04: an exam with 200 MBq [68Ga]Ga-FAPI-2/4 corresponds to an equivalent dose of approx. 3-4 mSv [330].
FAPI-46: the whole body dose for an administration of 200 MBq was 1.56± 0.26 mSv .[335]
[18F]F-FAPI: for FAPI-74 the effective dose of [18F]AlF-FAPI-74 was 2.4-2.8 mSv for a 200 MBq exam.
A normal FAPI-PET scan shows high tracer presence in the renal pelvis and the bladder. Low uptake is seen in the oral mucosa, the salivary glands, a higher accumulation can be seen in the uterus. Future evaluations have to analyse whether this uptake in the uterus is dependent on the menstrual cycle.
Healing wounds after trauma or surgery may also show physiological activation of fibroblasts leading to enhanced tracer uptake. The same holds true for non-oncologic diseases with remodelling of the extracellular matrix. Although this needs careful interpretation in cancer patients, it also presents an opportunity for an application of the method in a variety of the above-mentioned non-malignant diseases.
There is no need for fasting. Patients should be hydrated with oral intake of 500 ml water. Voiding is needed immediately before the image acquisition.