68Ga-fibroblast activation protein inhibitors (FAPIs) 2, 4, and 46 have already been proposed as promising PET tracers However, the short half-life of 68Ga (68 min) creates problems with manufacture and delivery 18F (half-life, 110 min) labeling would result in a more practical large-scale production, and a cold-kit formulation would improve the spontaneous availability The NOTA chelator ligand FAPI-74 can be labeled with both 18F-AlF and 68Ga Here, we describe the in vivo evaluation of 18F-FAPI-74 and a proof of mechanism for 68Ga-FAPI-74 labeled at ambient temperature Methods: In 10 patients with lung cancer, PET scans were acquired at 10 min, 1 h, and 3 h after administration of 259 ± 26 MBq of 18F-FAPI-74 Physiologic biodistribution and tumor uptake were semiquantitatively evaluated on the basis of SUV at each time point Absorbed doses were evaluated using OLINDA/EXM, version 11, and QDOSE dosimetry software with the dose calculator IDAC-Dose, version 21 Identical methods were used to evaluate one examination after injection of 263 MBq of 68Ga-FAPI-74 Results: The highest contrast was achieved in primary tumors, lymph nodes, and distant metastases at 1 h after injection, with an SUVmax of more than 10 The effective dose per a 100-MBq administered activity of 18F-FAPI-74 was 14 ± 02 mSv, and for 68Ga-FAPI-74 it was 16 mSv Thus, the radiation burden of a diagnostic 18F-FAPI-74 PET scan is even lower than that of PET scans with 18F-FDG and other 18F tracers; 68Ga-FAPI-74 is comparable to other 68Ga ligands FAPI PET/CT supported target volume definition for guiding radiotherapy Conclusion: The high contrast and low radiation burden of FAPI-74 PET/CT favor multiple clinical applications Centralized large-scale production of 18F-FAPI-74 or decentralized cold-kit labeling of 68Ga-FAPI-74 allows flexible routine use

https://jnm.snmjournals.org/content/jnumed/62/2/201.full.pdf

FAPI-74 PET/CT Using Either 18F-AlF or Cold-Kit 68Ga Labeling: Biodistribution, Radiation Dosimetry, and Tumor Delineation in Lung Cancer Patients.

This prospective study aimed to evaluate the potential usefulness of [68Ga]Ga-DOTA-FAPI-04 positron emission tomography/computed tomography (PET/CT) in the oncological evaluation of patients presenting with inconclusive [18F]FDG PET/CT findings [68Ga]Ga-DOTA-FAPI-04 was performed in patients presenting with inconclusive [18F]FDG PET/CT findings Tumour uptake was quantified by the maximum standard uptake value (SUV) Histopathology or follow-up imaging served as the standard for the final diagnosis A total of 68 patients with inconclusive [18F]FDG PET/CT findings underwent additional [68Ga]Ga-DOTA-FAPI-04 PET/CT Of them, 18 (265%) were for discrimination of mass lesions detected on conventional imaging, 6 (88%) for detection of the unknown primary site in biopsy-proven metastatic malignancy, 21 (309%) for the staging of cancer, and the other 23 (338%) for evaluation of suspected disease recurrence Most of the primary and metastatic lesions demonstrated higher uptake of [68Ga]Ga-DOTA-FAPI-04 than did [18F]FDG, which resulted in favourable tumour-to-background contrast in various types of cancer As a result, [68Ga]Ga-DOTA-FAPI-04 PET/CT identified suspicious mass lesions with an accuracy of 12/18 (667%), detected the primary site in 4/6 patients (667%) with unknown malignancy, upgraded tumour staging in 7/21 patients (333%), and detected disease recurrence in 20/23 patients (870%) In patients undergoing oncological evaluation with inconclusive [18F]FDG PET/CT findings, [68Ga]Ga-DOTA-FAPI-04 may have a complementary role in discriminating mass lesions on conventional imaging, locating the primary site of unknown malignancy, modifying tumour staging, and detecting suspected disease recurrence Nevertheless, careful attention should be paid when reading the [68Ga]Ga-DOTA-FAPI-04 PET/CT images in tumours complicated with inflammation

Usefulness of [68Ga]Ga-DOTA-FAPI-04 PET/CT in patients presenting with inconclusive [18F]FDG PET/CT findings

Fibroblast activation protein (FAP), a membrane-anchored peptidase, is highly expressed in cancer-associated fibroblasts in more than 90% of epithelial tumors and contributes to progression and worse prognosis of different cancers. Therefore, FAP is considered a promising target for radionuclide-based approaches for diagnosis and treatment of tumors and for the diagnosis of nonmalignant diseases associated with a remodeling of the extracellular matrix. Accordingly, a variety of quinolone-based FAP inhibitors (FAPIs) coupled to chelators were developed displaying specific binding to human and murine FAP with a rapid and almost complete internalization. Because of a high tumor uptake and a very low accumulation in normal tissues, as well as a rapid clearance from the circulation, a high contrast is obtained for FAPI PET/CT imaging even at 10 min after tracer administration. Moreover, FAPI PET/CT provides advantages over 18F-FDG PET/CT in several tumor entities for initial staging and detection of tumor recurrence and metastases, including peritonitis carcinomatosa.

https://jnm.snmjournals.org/content/jnumed/62/2/160.full.pdf

The Latest Developments in Imaging of Fibroblast Activation Protein

Pancreatic ductal carcinoma (PDAC) is a highly lethal cancer, and early detection and accurate staging are critical to prolonging survival. PDAC typically has a prominent stroma including cancer-associated fibroblasts that express fibroblast activation protein (FAP). FAP is a new target molecule for PET imaging of various tumors. In this retrospective study, we describe the clinical impact of PET/CT imaging using 68Ga-labeled FAP-inhibitors (68Ga-FAPI PET/CT) in 19 patients with PDAC (7 primary, 12 progressive/recurrent). Methods: All patients underwent contrast-enhanced CT (ceCT) for TNM staging before 68Ga-FAPI PET/CT imaging. PET scans were acquired 60 min after administration of 150–250 MBq of 68Ga-labeled FAP-specific tracers. To characterize 68Ga-FAPI uptake over time, additional scans after 10 or 180 min were acquired in 6 patients. SUVmax and SUVmean values of PDAC manifestations and healthy organs were analyzed. The tumor burden according to 68Ga-FAPI PET/CT was compared with TNM staging based on ceCT and changes in oncologic management were recorded. Results: Compared with ceCT, 68Ga-FAPI PET/CT results led to changes in TNM staging in 10 of 19 patients. Eight of 12 patients with recurrent/progressive disease were upstaged, 1 was downstaged, and 3 had no change. In newly diagnosed PDAC, 1 of 7 patients was upstaged, and the staging of 6 patients did not change. Changes in oncologic management occurred in 7 patients. Markedly elevated uptake of 68Ga-FAPI in PDAC manifestations after 1 h was seen in most cases. Differentiation from pancreatitis based on static imaging 1 h after injection was challenging. With respect to imaging after multiple time points, PDAC and pancreatitis showed a trend for differential uptake kinetics. Conclusion:68Ga-FAPI PET/CT led to restaging in half of the patients with PDAC and most patients with recurrent disease compared with standard of care imaging. The clinical value of 68Ga-FAPI PET/CT should be further investigated.

https://jnm.snmjournals.org/content/jnumed/62/6/779.full.pdf

Impact of 68Ga-FAPI PET/CT Imaging on the Therapeutic Management of Primary and Recurrent Pancreatic Ductal Adenocarcinomas.

This study aimed to evaluate the potential utility of [68Ga]Ga-FAPI-04 PET/CT for diagnosing primary and metastatic lesions in patients with liver cancer, as well as to compare it with contrast-enhanced CT (CE-CT), liver MRI, and [18F]-FDG PET/CT. We performed a single-center post hoc retrospective analysis of data obtained from a prospective parent study (NCT04416165). This study included 34 patients diagnosed with or suspected hepatic lesions who underwent concomitant [68Ga]Ga-FAPI-04 and [18F]-FDG/CT scans. Moreover, these patients underwent liver MRI (n = 34) and CE-CT (n = 25). Histopathologic (n = 62) or radiographic follow-up (n = 128) served as the reference standard for the final diagnosis. Among the 34 patients, 20, 12, and 2 patients presented with hepatocellular carcinomas, intrahepatic cholangiocarcinomas, and benign hepatic nodules, respectively. The sensitivities of CE-CT, MRI, [68Ga]Ga-FAPI-04, and [18F]-FDG/CT for detecting primary liver tumors were 96%, 100%, 96%, and 65%, respectively. Regarding the diagnosis of all intrahepatic lesions, the per-lesion detection rate of [68Ga]Ga-FAPI-04 PET/CT was slightly lower than that of MRI (85% vs. 100%, P = 0.34) and significantly higher than that of [18F]-FDG PET/CT (85% vs. 52%, P < 0.001). Regarding the diagnosis of all malignant lesions (including extrahepatic disease), the tumor detection rate of [68Ga]Ga-FAPI-04 PET/CT was 87.4%, which was significantly higher than that of [18F]-FDG PET/CT (65.0%, P < 0.001). Our findings indicate that the sensitivity of [68Ga]Ga-FAPI-04 PET/CT to correctly identify primary liver tumors and metastatic lesions is equivalent to that of CE-CT and liver MRI. Moreover, [68Ga]Ga-FAPI-04 PET/CT is better at identifying liver lesions than [18F]-FDG PET/CT, and its use may improve tumor staging, recurrence detection, and implementation of necessary treatment modifications.

Imaging fibroblast activation protein in liver cancer: a single-center post hoc retrospective analysis to compare [68Ga]Ga-FAPI-04 PET/CT versus MRI and [18F]-FDG PET/CT

We evaluated the potential usefulness of [68Ga]Ga-DOTA-FAPI-04 positron emission tomography/computed tomography (PET/CT) for the diagnosis of primary and metastatic lesions in various types of cancer, compared with [18F] FDG PET/CT. A total of 75 patients with various types of cancer underwent contemporaneous [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT either for an initial assessment or for recurrence detection. Tumour uptake was quantified by the maximum standard uptake value (SUVmax). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of [18F] FDG and [68Ga]Ga-DOTA-FAPI-04 PET/CT were calculated and compared to evaluate the diagnostic efficacy. The study cohort consisted of 75 patients (47 males and 28 females; median age, 61.5 years; age range, 32–85 years). Fifty-four patients with 12 different tumour entities underwent paired [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT for initial assessment, while the other 21 patients underwent paired scans for recurrence detection. [68Ga]Ga-DOTA-FAPI-04 PET/CT was able to clearly identify 12 types of malignant tumours with favourable tumour-to-background contrast, which resulted in a higher detection rate of primary tumours than did [18F] FDG PET/CT (98.2% vs. 82.1%, P = 0.021). Meanwhile, [68Ga]Ga-DOTA-FAPI-04 PET/CT showed a better sensitivity than [18F] FDG PET/CT in the detection of lymph nodes (86.4% vs. 45.5%, P = 0.004) and bone and visceral metastases (83.8% vs. 59.5%, P = 0.004). [68Ga]Ga-DOTA-FAPI-04 PET/CT showed a superior diagnostic efficacy than [18F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer, especially in identifying liver metastases, peritoneal carcinomatosis, and brain tumours.

Comparison of [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer.

This study aimed to investigate the diagnostic performance of [68Ga]Ga-FAPI PET/CT for primary and metastatic pancreatic carcinoma lesions and compare the results with those of [18F]-fluorodeoxyglucose ([18F]FDG) PET/CT. Patients with suspected or diagnosed pancreatic malignancy, who underwent contemporaneous [18F]FDG and [68Ga]Ga-FAPI PET/CT between June 2020 and January 2021, were retrospectively analyzed. Routine contrast-enhanced CT (CE-CT) is performed in all patients as standardized care. Findings were confirmed by histopathology or radiographic follow-up. We compared radiotracer uptake, diagnostic performance, and TNM (tumor-node-metastasis) classifications. We evaluated 36 participants (25/36 men; median age, 60 years), including 26 patients with pancreatic malignancies and ten patients with pancreatic benign lesions. [68Ga]Ga-FAPI PET/CT showed higher radiotracer uptake and higher sensitivity than [18F]FDG PET/CT in evaluating primary tumors (SUVmax, 21.4 vs. 4.8; sensitivity, 100% vs. 73.1%), involved lymph nodes (SUVmax, 8.6 vs. 2.7; sensitivity, 81.8% vs. 59.1%), and metastases (SUVmax, 7.9 vs. 3.5; sensitivity, 91.5% vs. 44.0%); Compared with [18F]FDG, [68Ga]Ga-FAPI PET/CT upstaged six patients’ TNM staging (6/23, 26.1%) and changed two patients’ clinical management (2/23, 8.7%). Compared with CE-CT, [68Ga]Ga-FAPI PET/CT upgraded TNM staging in five patients (5/23, 21.7%) and changed the therapeutic regimen in only one patient (1/23, 4.3%). Intense [68Ga]Ga-FAPI uptake was observed throughout the pancreas in 12/26 pancreatic malignancies; dual-time point [68Ga]Ga-FAPI PET/CT may differentiate pancreatitis from malignancy. Compared with [18F]FDG PET/CT, [68Ga]Ga-FAPI PET/CT shows higher sensitivity in detecting primary pancreatic tumors, involved lymph nodes, and metastases and is superior in terms of TNM staging. Prospective trials with larger patient population are needed to evaluate whether [68Ga]Ga-FAPI PET/CT could elicit treatment modification in pancreatic cancer when compared with standard of care imaging.

Positron emission tomography and computed tomography with [68Ga]Ga-fibroblast activation protein inhibitors improves tumor detection and staging in patients with pancreatic cancer.

Evaluation of disease activity in Takayasu arteritis (TA) is challenging because clinical, biological, and imaging data do not always correlate. In this case, a 19-year-old woman with TA underwent 18F-FDG PET/CT for evaluating disease activity. However, no abnormal 18F-FDG uptake was observed in the large arteries. Follow-up with 68Ga-FAPI PET/CT showed intense activity in the mildly thickened walls of bilateral carotid, subclavian arteries, and thoracic and abdominal aorta. This case presented an example where 68Ga-FAPI outperformed 18F-FDG for detecting active inflammation of TA. Therefore, 68Ga-FAPI PET/CT may allow monitoring of disease activity and facilitate selecting the optimal therapy for TA patients.

68Ga-FAPI PET/CT Versus 18F-FDG PET/CT for the Evaluation of Disease Activity in Takayasu Arteritis.

Ankylosing spondylitis represents an inflammatory arthropathy with a predilection for the axial skeleton. We reported 68Ga-FAPI PET/CT finding of ankylosing spondylitis in a 65-year-old patient with rectal cancer. In addition to accumulating in primary tumor and metastatic lymph nodes, increased 68Ga-FAPI uptake was also observed in the sacroiliac and costovertebral joints, indicating sacroiliitis and spondylitis. However, no abnormal 18F-FDG uptake was observed in the inflammatory lesions. This case highlighted that 68Ga-FAPI PET/CT is useful for the evaluation of inflammatory conditions in ankylosing spondylitis.

Long Zhao

Papers

Comparison of [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer.

Positron emission tomography and computed tomography with [68Ga]Ga-fibroblast activation protein inhibitors improves tumor detection and staging in patients with pancreatic cancer.

68Ga-FAPI PET/CT Versus 18F-FDG PET/CT for the Evaluation of Disease Activity in Takayasu Arteritis.

Increased 68Ga-FAPI Uptake in Ankylosing Spondylitis in a Patient With Rectal Cancer.