The comparative utility of FAPI-based PET radiotracers over [(18)F]FDG in the assessment of malignancies.

Am J Nucl Med Mol Imaging 2024;14(4):190-207 www.ajnmmi.us /ISSN:2160-8407/ajnmmi0156308 Review Article The comparative utility of FAPI-based PET radiotracers over [18F]FDG in the assessment of malignancies Shashi B Singh1, Bimash B Shrestha2, Om H Gandhi3, Rajendra P Shah4, Vaibhavi Mukhtiar5, Cyrus Ayubcha6, Vineet Desai6, Christine E Eberts7, Pranita Paudyal8, Goody Jha9, Anurag Singh10, Yangyang Shi11, Tushar Kumar12 Stanford University School of Medicine, Stanford, CA 94305, USA; 2KIST Medical College, Lalitpur, Bagmati 44700, Nepal; 3Hospital of The University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA; 4Department of Cardiology, HCA Houston Healthcare, Houston, TX 77004, USA; 5Saint Vincent Hospital, 123 Summer Street, Worcester, MA 01608, USA; 6Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; 7University of California, San Diego School of Medicine, 9500 Gilman Dr, La Jolla, CA 92093, USA; 8Bridgeport Hospital, 267 Grant Street, Bridgeport, CT 06610, USA; 9University of California Davis Medical Center, 4301 X Street, Sacramento, CA 95817, USA; 10Trijuddha Mahavir Prasad Raghuvir Ram Madhyamik Vidyalaya, Birgunj, Parsa 44300, Nepal; 11 University of Arizona College of Medicine, 1501 N Campbell Avenue, Tucson, AZ 85724, USA; 12University of Washington Medical Center, Main Hospital, 1959 NE Pacific Street, Seattle, WA 98195, USA 1 Received March 3, 2024; Accepted July 28, 2024; Epub August 25, 2024; Published August 30, 2024 Abstract: Fibroblast activation protein (FAP) is a type II transmembrane serine protease overexpressed in cancer-associated fibroblasts (CAFs) and has been associated with poor prognosis. PET/CT imaging with radiolabeled FAP inhibitors (FAPI) is currently being studied for various malignancies. This review identifies the uses and limitations of FAPI PET/CT in malignancies and compares the advantages and disadvantages of FAPI and 18F-fluorodeoxyglucose ([18F]FDG). Due to high uptake, rapid clearance from the circulation, and limited uptake in normal tissue, FAPI tumor-to-background contrast ratios are equivalent to or better than [18F]FDG in most applications. In several settings, FAPI has shown greater uptake specificity than [18F]FDG and improved sensitivity in detecting lymph node, bone, and visceral tissue metastases. Therefore, FAPI PET/CT may be complementary in distinguishing pathological lesions with conventional imaging, determining the primary site of malignancy, improving tumor staging, and detecting disease recurrence, especially in patients with inconclusive [18F]FDG PET/CT findings. Nevertheless, FAPI has limitations, including certain settings with non-specific uptake, modified uptake with age and menopause status, challenges with clinical access, and limited clinical evidence. Keywords: Fibroblast activation protein (FAP), fibroblast activation protein inhibitor (FAPI), positron emission tomography (PET), [18F]fluorodeoxyglucose ([18F]FDG), cancer, malignancy, diagnosis Introduction Molecular imaging allows for visualizing and characterizing biological processes at the tissue level [1]. Positron emission tomography (PET), a molecular imaging modality, utilizes radionuclide-labeled biomarkers, also known as radiotracers, to evaluate tissue function. PET can identify functional changes earlier than structural imaging modalities and capture the functional state of tissues [2]. The most commonly used PET radiotracer is 18 F-fluorodeoxyglucose ([18F]FDG), a glucose analog. [18F] FDG uptake directly correlates with cellular metabolic rate and GLUT transporter expression [3], making [18F] FDG PET/CT valuable for imaging malignant, infectious, and inflammatory processes due to increased [18F]FDG uptake in cells with elevated glycolytic activity, such as cancer cells or activated granulocytes [4, 5]. However, [18F]FDG lacks optimal specificity for malignancies, resulting in low tumor-to-background ratios (TBRs) and low sensitivity for certain cancers [6]. To address these limitations, researchers have focused on developing new radiotracers, including radiolabeled fibroblast activation protein inhibitors (FAPIs) [6, 7]. Fibroblast activation protein (FAP) is a 760-amino-acid, type II transmembrane glycoprotein that belongs to the serine protease family. It is expressed in stromal fibroblasts in more than 90% of epithelial malignancies and malignant cells in glioblastoma, breast, colorectal, cervical, pancreatic, and oral squamous cell carcinomas [8-10]. Overexpression of FAP is linked to increased local tumor invasiveness, lower survival, and poor prognosis [9-11]. Activated fibroblasts and FAPs are only expressed in reactive tumor stroma or fibrosis. The normal stroma contains only a small number of quiescent fibroblasts with low or undetectable FAP expression [12]. This selective expression makes FAP an excellent biomarker for identifying and targeting tumors. One of the promising applications of targeting FAP is through the use of FAP inhibitors (FAPI). These inhibitors can be radiolabeled and used in PET imaging for targeted imaging of various cancers (Figure 1) [13-15]. While most radiotracers are utilized only diagnostically due to notable physiological uptake, the highly selective expression of FAP allows for paired theragnostic approaches. Much of the current work in FAPI research is performed with quinoline-based, small-molecule FAPI deriva- https://doi.org/10.62347/JXZI9315 FAPI PET in malignancies Figure 1. Maximum-intensity projection images of [68Ga]Ga-FAPI PET/CT scans demonstrating 15 distinct histologically proven tumor types, with the tumors sorted based on their uptake levels in descending order. Abbreviations used to represent specific tumor entities: Ca (cancer), CCC (cholangiocellular carcinoma), CUP (carcinoma of unknown primary), MTC (medullary thyroid cancer), and NET (neuroendocrine tumor). Adapted from Journal of Nuclear Medicine [15]. © by the Society of Nuclear Medicine and Molecular Imaging, Inc. tives with a high affinity for FAP and a superior pharmacokinetics [10]. To utilize their unique imaging properties, FAPI has been labeled with 68Gallium (68Ga) and 18Fluorine (18F). The chemical structures of some FAPI compounds are shown in Figure 2 [16]. 191 The first FAPI tracers introduced in clinical research were labeled with 68Ga, which has a relatively short half-life of 68 minutes; this limited the accessibility of [68Ga]Ga-FAPI in centers without onsite production [10]. 18F has a longer half-life of 109.8 minutes and is easier to produce, which Am J Nucl Med Mol Imaging 2024;14(4):190-207 FAPI PET in malignancies Comparing FAPI PET/CT and [18F]FDG PET/CT The studies included in this review comparing FAPI PET/CT and [18F]FDG PET/CT in malignancies were evaluated based on their performance in four main categories: tracer uptake, tumor-to-background ratio (TBR), detection of primary tumors, and detection of metastases. The results are summarized in Table 1. (...truncated)