Advances in the Development of Positron Emission Tomography Tracers for Improved Detection of Differentiated Thyroid Cancer

Simple Summary This review discusses new radiotracers for diagnosing and treating thyroid cancer. It focuses on PSMA-based tracers, FAPI-based tracers, RGD-based tracers, and 18F-TFB. These tracers show promise in detecting thyroid cancer, especially in challenging cases. They offer better accuracy and help in choosing the right treatment. Further research is needed, especially on the promising 18F-TFB and FAP-targeting tracers, to improve thyroid cancer staging and treatment outcomes. Abstract Thyroid cancer poses a significant challenge in clinical management, necessitating precise diagnostic tools and treatment strategies for optimal patient outcomes. This review explores the evolving field of radiotracers in the diagnosis and management of thyroid cancer, focusing on prostate-specific membrane antigen (PSMA)-based radiotracers, fibroblast activation protein inhibitor (FAPI)-based radiotracers, Arg-Gly-Asp (RGD)-based radiotracers, and 18F-tetrafluoroborate (18F-TFB). PSMA-based radiotracers, initially developed for prostate cancer imaging, have shown promise in detecting thyroid cancer lesions; however, their detection rate is lower than 18F-FDG PET/CT. FAPI-based radiotracers, targeting fibroblast activation protein highly expressed in tumors, offer potential in the detection of lymph nodes and radioiodine-resistant metastases. RGD-based radiotracers, binding to integrin αvβ3 found on tumor cells and angiogenic blood vessels, demonstrate diagnostic accuracy in detecting radioiodine-resistant thyroid cancer metastases. 18F-TFB emerges as a promising PET tracer for imaging of lymph node metastases and recurrent DTC, offering advantages over traditional methods. Overall, these radiotracers show promise in enhancing diagnostic accuracy, patient stratification, and treatment selection in differentiated thyroid cancer, warranting further research and clinical validation. Given the promising staging capabilities of 18F-TFB and the efficacy of FAP-targeting tracers in advanced, potentially dedifferentiated cases, continued investigation in these domains is justified.


Introduction
Thyroid cancer is a common type of cancer that accounts for 3% of all cancer cases worldwide.Proper diagnosis and staging are important for determining the best treatment options and improving patient outcomes.Traditional imaging techniques like ultrasound and computed tomography (CT) have been useful for evaluating thyroid nodules and assessing thyroid cancer.However, using PET tracers like 18 F-FDG PET/CT can provide more accurate results in detecting and characterizing thyroid cancer lesions.According to the American Thyroid Association (ATA) guidelines, advanced imaging studies like CT and MRI with intravenous contrast should be used alongside ultrasound for preoperative assessment in patients with suspected advanced thyroid disease [1].The European Association of Nuclear Medicine (EANM) recommends 18 F-FDG PET/CT for differentiated thyroid cancer (DTC) patients with rising Tg levels to aid in detecting recurrent/metastatic disease and determining the tumor's biological behavior [2].
Follow-up DxWBS in combination with Tg measurement is useful for evaluating therapy response and identifying patients with iodine-avid metastatic disease.Brain MRI is recommended in advanced DTC cases due to the potential presence of brain metastases, especially in the absence of neurological signs or symptoms, as 18 F-FDG PET/CT is not reliable in the brain due to high glucose metabolism.The most commonly used PET tracers are 18 F-FDG and iodine-124 ( 124 I).Iodine-124 is a radionuclide that emits positrons, making it suitable for NIS imaging with PET.However, 124 I has some limitations: (1) its 4.2-day half-life and low positron yield lead to high radiation exposures, making it less desirable for diagnostic imaging; (2) its high-energy single photon emissions (0.6-1.7 MeV) can compromise image quality; and (3) its high positron emission energy results in maximum tissue travel of >6 mm before annihilation, negatively impacting imaging resolution.In clinical settings, 18 F-FDG PET/CT proves valuable as a prognostic factor for RAI treatment response in metastatic DTC patients, with high 18 F-FDG uptake serving as an independent negative prognostic factor for overall survival.
In recent times, much effort has been spent on trying out numerous new tracers for imaging in various clinical stages of DTC in order to advance imaging sciences, especially where ultrasound and 18 F-FDG PET/CT are not sufficient.This has resulted in numerous publications on various situations, without a good overview of the performance of different tracers in similar situations currently available in the literature.Hence, this review aims to comprehensively evaluate the literature on new tracers for different clinical indications in thyroid cancer, such as detecting lymph node metastases, TENIS (thyroglobulin elevation/negative iodine scintigraphy) syndrome, recurrent or persistent disease, and distant metastases in DTC.

Prostate-Specific Membrane Antigen-Based Radiotracers for Differentiated Thyroid Cancer
Prostate-specific membrane antigen (PSMA) is a protein that was first discovered to be overproduced in prostate cancer cells.Recently, the United States Food and Drug Administration approved 68 Ga-PSMA-11 PET imaging to detect the potential spread or recurrence of prostate cancer in patients. 68Ga-PSMA PET/CT is now being used in clinical practice and trials for prostate cancer diagnosis.Although PSMA expression has been reported in the tumor-associated endothelium of various malignancies, including colon, breast, and adrenocortical cancers, its expression in thyroid tumors has not been systematically studied.Recently, several studies found unexpected PSMA radiotracer uptake by thyroid tumors, including radioiodine-refractory (RAI-R) DTC, which has led to an interest in studying 68 Ga-PSMA PET/CT for thyroid cancer.
PSMA is a type 2 transmembrane protein, and it facilitates endothelial cell invasion through the extracellular matrix by interacting with the cytoskeleton via integrin signaling and actin-binding protein Filamin A. Therefore, it is overexpressed on the endothelial cells of the tumor neovasculature in several solid [3].It has been found through functional studies that PSMA plays a role in tumor angiogenesis and is part of a self-regulating loop that involves β1-integrin and p21-activated kinase 1 (PAK1).This has led to the hypothesis that 68 Ga-PSMA PET/CT could be useful in detecting thyroid cancer. 68Ga-PSMA PET/CT could aid in detecting a recurrence in RAI-R patients, identifying metastases in TENIS patients, and selecting patients who could benefit from PSMA-targeted radionuclide therapy ( 177 Lu-PSMA-617), particularly those with metastatic dedifferentiated thyroid cancer.
Several preclinical studies have examined the expression of PSMA in thyroid tissue, various types of thyroid cancer, lymph node metastases, in vivo small animal models, its potential role as a biomarker for tumor aggressiveness, and its correlation with patients' RAI positivity or negativity.Bychkov et al. (2017) conducted a study of 267 individuals and found that PSMA expression was commonly present in thyroid tumor microvessels, but absent in benign tissue [4].PSMA expression varied significantly, ranging from 19% in benign tumors to over 50% in thyroid cancer, with a high degree of heterogeneity.PSMA expression was not found to be directly associated with endothelial cell proliferation, as confirmed by immunostaining with the endothelial marker CD105.Heitkotter and colleagues also reported similar outcomes, where overall PSMA expression was significantly higher in malignant tumors (57.1%; n = 36/63) than in benign diseases (13.2%; n = 5/38).
Research findings indicate that the expression of PSMA varies across different types of thyroid cancer.According to the study by Bychkov et al., the expression of PSMA was reported to be 19% in follicular adenomas, 46% (n = 24/52) in follicular thyroid carcinoma (FTC), and 51% in papillary thyroid carcinoma (PTC) (n = 61/120) [4].These percentages were consistent with another study, revealing 40% (n = 4/10) in FTC and 58% (n = 18/31) in PTC.Santhanam et al. investigated the expression of PSMA in local metastatic thyroid cancer in lymph nodes.All three lymph node samples investigated stained positive for PSMA expression in the neovasculature [5].
In their exploration of PSMA expression as a biomarker for DTC aggressiveness and outcome prediction, Sollini et al. conducted a study involving 59 cases [6].The study found that PSMA expression varied among the cases analyzed.The percentage of PSMA expression was ≤10% in 17 cases, 11 to 79% in 31 cases, and ≥80% in 11 cases.The multivariate analysis identified several significant predictors of distant metastases, including age, sex, histotype, vascular invasion, T and N parameters, and PSMA positivity.The final multivariate model that predicted RAI-R included the stage, high PSMA expression (≥80%), and the interaction between moderate PSMA expression (11 to 79%) and the stage.Ciappucino's findings complemented this research by indicating that patients aged ≥ 55 years, and those with large primary tumors (>40 mm) or aggressive subtypes, had a higher mean immunoreactive score (IRS), which correlated with structural disease at the last follow-up [7].Strong PSMA expression (IRS ≥ 9) was associated with a shorter progression-free survival (PFS).Bychkov et al. reported PSMA expression's correlation with tumor size (p = 0.02) and vascular invasion in FTC (p = 0.03), while no significant associations were observed with other baseline histological and clinical parameters [4].
Feng et al. conducted a comprehensive investigation employing Western blot, PCR, and [68Ga]Ga-PSMA uptake experiments on cell lines, complemented by in vivo small animal imaging [8].Their study revealed a significant correlation between 68 Ga-PSMA imaging and tumor burden, as evidenced by correlations with 18 F-FDG PET/CT (8.08 ± 7.74 and 5.67 ± 4.23, p = 0.01) and thyroglobulin (Tg) levels (307.1 ± 183.4 vs. 118.0± 116.1, p = 0.002).Notably, the research indicated an association between increasing PSMA expression and decreasing thyroid cancer differentiation.However, the 68 Ga-PSMA uptake in thyroid cancer patients was not significantly linked solely to the degree of thyroid cancer differentiation but also demonstrated associations with the metabolic activity and tumor burden, as reflected by the 18 F-FDG PET/CT and Tg levels.In a parallel study, Ciappuccini et al. investigated PSMA expression in neck persistent/recurrent disease (PRD) utilizing immunohistochemistry and its correlation with RAI or 18 F-FDG uptake, along with patient outcomes in a cohort of 44 individuals [7].The quantification of PSMA expression using the immunoreactive score (IRS) revealed that 68% of patients exhibited at least one PSMA-positive lesion (IRS ≥ 2), with comparable proportions in RAI-positive and RAI-negative patients (75% vs. 66%).In RAI-negative patients, however, the prevalence of PSMA-positive disease (79% vs. 25%, p < 0.01) and the mean IRS (4.0 vs. 1.0, p = 0.01) were notably higher in 18 F-FDG-positive compared to 18 F-FDG-negative patients.
Several imaging studies have been conducted using PSMA-based radiotracers such as 68 Ga-PSMA-11 (68Ga-HBED-CC-PSMA) and 18 F-DCFPyL (as shown in Tables 1 and 2).The efficacy of 68 Ga-PSMA-11 has been studied for various purposes such as detecting DTC metastases, identifying patients suitable for PSMA-targeted radionuclide therapy, diagnosing patients with RAI-R DTC, for patients with TENIS, and detecting patients with elevated Tg or anti-Tg antibodies.
In a case report by Verburg et al., strong uptake was seen in the cervical lymph nodes and pulmonary metastases in a patient with RAI-R DTC [9].In a study by Verma et al.
A prospective study was conducted on patients with iodine-negative and FDG-positive metastasized DTC [11].The study found that 68 Ga-PSMA-11 PET/CT was able to successfully identify metastatic disease in five out of six patients, with all 42 lesions confirmed by 18 F-FDG PET/CT or conventional CT imaging.Using the 68 Ga-PSMA-11 PET/CT, all the tumor lesions identified with the 18 F-FDG PET/CT imaging could be visualized in three of the five patients.In two patients, only the most prominent lesions detected with the 18 F-FDG PET/CT imaging were visualized by the 68 Ga-PSMA-11 PET/CT.
In a prospective pilot study by Verma et al., PSMA expression was detected in two TENIS patients using 68 Ga-PSMA-11 PET/CT [10].The lesions were found in the bones and lungs, and the 68 Ga-PSMA PET/CT localized a lesion in each patient similar to the 18 F-FDG PET/CT results.In a later study, PSMA expression was found in five out of nine patients with TENIS [12].A total of fourteen lesions were detected on the CT scan, and the 68 Ga-PSMA PET/CT detected nine of them (64.28%), with SUVmax ranging from 10.1 to 45.67 and median SUVmax of 16.31.On the other hand, 18 F-FDG PET/CT was positive in 11 out of 14 lesions (78.57%).The lesions that showed PSMA uptake were localized in bones (five out of nine) and lungs (four out of nine).Two lesions localized in the iliac crest and acetabulum were missed on the 18 F-FDG PET/CT but were seen on CT and the 68 Ga-PSMA PET/CT.In a case study with one patient, 68 Ga-PSMA-11 PET/CT was used to detect metastases in TENIS [13].Intense radiotracer uptake was found in mediastinal and left supraclavicular lymph nodes, brain metastases, bilateral lung nodules, and skeletal sites.The patient also underwent 18 F-FDG PET/CT, which demonstrated similar findings; however, the number of lesions detected in the brain was fewer compared to 68 Ga-PSMA PET/CT.In the investigation of 68 Ga-PSMA-11 for detecting DTC metastases, Lawhn-Heath et al. (n = 7) found a detection rate of 93.8% for 18F-FDG PET/CT and 53.1% for 68 Ga-PSMA PET/CT [14].The median lesion SUVmax was 9.0 for the 18 F-FDG PET/CT (range 3.5-28.4)and 9.2 for the 68 Ga-PSMA PET/CT (range 2.0-27.8).The 68 Ga-PSMA PET/CT had the highest detection rate for FTC, reaching 80.0%.In another study (n = 10), 68 Ga-PSMA-11 PET/CT successfully identified all 64 lesions, each of which was also confirmed by CT [15].In contrast, 131 I SPECT/CT detected 55 out of the 64 lesions, with discrepant lesions localized in the lung (44.4%), brain (22.2%), postoperative thyroid bed (11.1%), lymph nodes (11.1%), and bone (11.1%).The degree of agreement among the observers was notably high for both radiotracers.For the 68 Ga-PSMA-11, the agreement had a κ of 0.98 (95% CI, 0.80-0.91),whereas for the 131 I, it was slightly lower (κ = 0.86; 95% CI, 0.71-0.76).
In their study on RAI-R DTC, de Vries et al. (n = 5) observed tracer uptake suggestive of distant metastases in all 68 Ga-PSMA-11 PET/CT scans [16].Three patients underwent comparative imaging with 18 F-FDG PET/CT, revealing additional lesions on 68 Ga-PSMA PET/CT in two patients.Shi et al. prospectively enrolled 23 DTC and 17 RAI-R DTC patients [17].The study found that the detection rates of DTC and RAI-R DTC were lower with 68 Ga-PSMA-11 PET/CT than with 18F-FDG PET/CT (60.00% vs. 90.00%for DTC and 59.38% vs. 96.88%for RAI-R DTC).Immunohistochemistry also revealed that RAI-R DTC had significantly higher PSMA expression levels than DTC, but this difference did not correlate significantly with the SUVmax on 68 Ga-PSMA-11 PET/CT.
In a separate study, Santhanam et al. (2020) investigated the localization of metastases with 18 F-DCFPyL PET/CT in three patients with metastatic RAI-R DTC [5].The following are the results of two patient scans using 18F-DCFPyl: In the first patient, the scan picked up activity in the retropharyngeal CT contrast-enhancing lymph node.The 18 F-DCFPyl scan showed a greater SUV (3.1) compared to the 18 F-FDG PET/CT (1.8).In the second patient, the 18 F-DCFPyl scan showed intense uptake in the L3 vertebra, which was not visible on the post-treatment 131 I whole-body scan or the 18 F-FDG PET/CT.An MRI scan of the lumbar spine confirmed the presence of a sclerotic-lytic lesion in that location, indicating metastatic disease.Singh et al. also presented a case study, in which 18 F-DCFPyl PET/CT was able to detect PTC [18].

Fibroblast Activation Protein Inhibitor-Based Radiotracers for Differentiated Thyroid Cancer
Fibroblast activation protein inhibitor (FAPI) is a relatively new tracer.In the pioneering study of Kratochwil (2019), 68 Ga-FAPI-04 showed tracer uptake in 28 different kinds of cancer [19].In recent years, 68 Ga-FAPI imaging has been explored for various purposes in different clinical settings with promising results [20].
Fibroblast activation protein (FAP) is a type II transmembrane serine protease and is highly expressed in more than 90% of epithelial tumors; it is closely associated with tumor invasion and metastasis [21].Using FAP as a target, different FAP inhibitors (FAPIs) have been developed.FAP is highly expressed on the cancer-associated fibroblasts' membrane but not in normal tissue.It is thus associated with tumor invasion, metastasis, angiogenesis, and prognosis [22].Its use has been investigated in the setting of detecting metastases for patients with RAI-R and patients with TENIS syndrome.
In the preclinical study conducted by Sun et al., it was observed that the presence of the BRAFV600E mutation correlated with heightened expression of cancer-associated fibroblast membrane proteins, including FAP [23].Consequently, the use of FAPI may offer enhanced accuracy compared to 18 F-FDG PET/CT, especially in patients with more aggressive disease manifestations.
Two case studies report on 68 Ga-FAPI PET/CT for diagnosing metastases in patients with TENIS syndrome.One case study presents the first case of TENIS syndrome with FAPIavid metastatic lesions.The 68 Ga-FAPI PET/CT localized abnormal foci at the laryngeal mass and bilateral pulmonary nodules [24].The second case study compares 18 F-FDG PET/CT with FAPi: Compared with 18 F-FDG PET/CT, the 68 Ga-FAPI PET/CT showed more and higher metabolic lesions, including lesions in the liver, bones, and abdominal lymph nodes [25].
The study with the most patients included is a retrospective study (n = 117) focused on comparing 68 Ga-DOTA.SA.FAPi and 18 F-FDG PET/CT in patients' RAI-R DTC.The 68 Ga-DOTA.SA.FAPi exhibited a superior detection rate for lymph nodes, liver, bowel, and brain metastases compared to the 18 F-FDG PET/CT [26].
In a study by Nourbakhsh et al. (2024) involving 14 patients with TENIS syndrome, the performance of 18 F-FAPI-46 was compared to 18 F-FDG PET/CT imaging [28].All the patients exhibited active lesions in both scans, with significantly lower SUVmax values in the liver and blood pool for the FAPI compared to the 18 F-FDG PET/CT (p = 0.001).Notably, the standard SUV of the hottest lesion to the liver exceeded three in all FAPI scans but only in half of the 18 F-FDG PET/CT scans, highlighting FAPI's consistent identification of high metabolic activity lesions.In one case, the FAPI detected pulmonary nodules (SUVmax = 3.8) missed by the 18 F-FDG PET/CT (SUVmax = 0.9), resulting in a 20% upstaging of patients.
In a study (n = 24) investigating 68 Ga-DOTA-FAPI-04 PET/CT, positive lesions were identified in 87.5% of patients, particularly in lung and lymph node metastases [29].In a case report, 68 Ga-DOTA-2P(FAPI)2 was also able to detect PTC in a patient with diffuse lymph node metastases after total thyroidectomy and multiple cycles of RIT [30].The tumor lesion became clearly visible with a good tumor-to-background ratio.

Arg-Gly-Asp-Based Radiotracers for Differentiated Thyroid Cancer
The tripeptide Arg-Gly-Asp (RGD) acid sequence has a high affinity and specificity for integrin αvβ3, a receptor found in various malignant tumors.RGD-based tracers have been developed for diverse imaging modalities, such as positron emission tomography, single photon emission computed tomography (SPECT), molecular magnetic resonance imaging, optical fluorescence, optical bioluminescence, photoacoustic imaging, and targeted contrast-enhanced ultrasound.RGDs have undergone testing in multiple cancer types, including melanoma, brain tumors, sarcoma, squamous cell carcinoma of the head and neck, glioblastoma multiforme, breast cancer, and rectal cancer.The versatility of RGD-based tracers reflects their potential utility across a spectrum of imaging strategies and cancer types.
The Arg-Gly-Asp (RGD) sequence has been identified for its ability to attach to the αvβ3 integrin found on the surface of angiogenic blood vessels or tumor cells.Integrin ανβ3 is essential for cell migration and invasion and plays an important role in tumor angiogenesis.Integrin ανβ3 expression is high on the surface of activated endothelial cells in newly formed blood vessels but is low in both resting endothelial cells and most normal organ systems, thus representing an interesting molecular marker for angiogenesis imaging.The RGD motif can be used to bind radiolabeled analogs.Thus, various radiolabeled derivatives of RGD peptides have been developed for angiogenesis imaging.Based on RNA-seq data from The Cancer Genome Atlas, the expression of αv and β3 integrin subunits is particularly high in thyroid cancer.Integrin αvβ3 overexpression in thyroid cancer is likely due to its presence on both the activated endothelial cells of the cancer neovasculature and the cancer cell surface, as shown by several reports documenting αvβ3 integrin expression in thyroid cancer cell lines [31].For DTC, RGD-based radiotracers have been investigated for the detection of DTC lymph node metastases, RAI-R patients, and patients with a negative post-therapy 131 I-scan.
The preclinical study of Cheng et al. (2016) investigated the antagonism of Arg-Gly-Asp (RGD)-binding integrin activity in three PTC cell lines (BCPAP, K1, and TPC1) [32].The research revealed that all three cell lines exhibited moderate-to-high expression of RGD-binding integrin heterodimers αvβ3 and αvβ5.Antagonizing these integrins resulted in a significant inhibitory effect on cell viability, stronger apoptotic responses in TPC1 cells, and substantial inhibition of migration and invasion across all three PTC cell lines.
There are two clinical studies investigating the diagnostic accuracy of RGD-based radiotracers for the detection of DTC.These are 18 F-AIF-NOTA-PRGD2 and 68 Ga-DOTA-RGD2.
Cheng et al. ( 2014) (n = 20) compared 18 F-AIF-NOTA-PRGD2 with 18 F-FDG PET/CT for the detection of lymph node metastases of DTC, revealing that although 18 F-AIF-NOTA-PRGD2 exhibited abnormal uptake in most DTC lymph node metastases, its diagnostic value was inferior to 18 F-FDG PET/CT [33].For all malignant lesions, the mean SUV for the 18 F-FDG PET/CT was significantly higher than that for the 18 F-AIF-NOTA-PRGD2 (p < 0.05).Another study aimed to compare the diagnostic accuracy of 68 Ga-DOTA-RGD2 PET/CT with 18 F-FDG PET/CT in RAI-R patients [34].In a prospective enrollment of 44 RAI-R DTC patients, the 68 Ga-DOTA-RGD2 PET/CT demonstrated an overall sensitivity of 82.3%, specificity of 100%, and accuracy of 86.4%, while the 18 F-FDG PET/CT showed a sensitivity of 82.3%, specificity of 50%, and accuracy of 75%.

[ 18 F]Tetrafluoroborate
In 2017, a new PET tracer was tested in healthy human subjects for the imaging of DTC: 18 F-tetrafluoroborate ( 18 F-TFB).This study showed promising results of using 18 F-TFB PET/CT for noninvasive NIS imaging, as 18 F-TFB can mimic iodide transport. 18F-TFB can go through the NIS receptor and gets trapped in thyroid cells. 18F-TFB has diagnostic potential in detecting (recurrent) differentiated thyroid cancer and cervical lymph node metastases.One indication for an 18 F-TFB PET/CT scan is the detection of pre-operative cervical lymph node metastases to avoid a second surgery.Another indication is to predict whether radioiodine therapy will be successful in a patient. 18F-TFB PET/CT has three advantages over 123 I-or 131 I-scintigraphy.First of all, 18 F-TFB is a positron emitter detected by PET, which is more sensitive than a gamma camera.Second, the scan takes place on the same day as the administration of the tracer, so patients do not have to attend an extra day (as is the case in iodine-123(131) scintigraphy).Third, it has a lower radiation dose.
Pre-clinical studies have been performed in xenograft mice and cell lines.These studies concluded that 18 F-TFB has specific uptake by the sodium/iodide symporter.Jarugeui-Osoro et al. showed a rapid accumulation of 18 F-TFB in FRTL-5 rat thyroid cells and in vivo in the thyroid and stomach [35].This was confirmed by Weeks et al. and Khoshnevisan et al. in NIS-expressing human colon cell [36,37].Diocou et al. found that 18 F-TFB was superior to I-123 due to better pharmacokinetics (faster tumor uptake and faster and more complete clearance from circulation) [38].Niu et al. illustrated the possibilities of 18 F-TFB in NIS-expressing cell lines for the diagnosis of stomach cancer [39].Goetz et al. provided further information on the time-activity curves and fitted kinetics for 18 F-TFB in mice [40].Jiang et al. assessed the influence of specific activity on tumor uptake in NIS-expressing C6-glioma xenograft tumors [41].Marti-Clement et al. conducted whole-body PET imaging in two non-human primates.It concluded that it is a very useful radiotracer in primates, with a characteristic biodistribution in organs expressing NIS [42].
In four clinical phase I studies with a total of 47 patients, 18 F-TFB PET/CT proved to be safe and effective in humans [43,44].In these clinical trials, the safety, pharmacokinetics, metabolism, biodistribution, and dosimetry were assessed [44]. 18F-TFB has a short half-life of 110 min, low-energy (Emax = 0.634 MeV), and high-yield (97%) positron emission [43].In human subjects, it showed rapid renal clearance and no uptake in bone and joints, meaning that 18 F-fluoride was not released in vivo after IV administration [43].Next to this, 18 F-TFB imaging was compared to 124 I PET/CT, 18 F-FDG PET/CT, and 131 I scintigraphy [43,45].The 18 F-TFB PET/CT showed higher sensitivity and accuracy than 131 I in whole-body scintigraphy and SPECT-CT.The 18 F-TFB PET/CT was not inferior to the 124 I PET/CT in detecting thyroid cancer and was able to detect metastases that were not found on the 124 I PET/CT [43].

Discussion
Studies have suggested that PSMA PET/CT is better than 18 F-FDG PET/CT in detecting lesions in bones and lungs.These radiotracers have also been linked to radioiodinerefractory thyroid cancer.Additionally, PSMA expression levels have been explored as potential biomarkers for predicting distant metastases and radioiodine therapy (RIT) outcomes, and their inclusion in multivariate models for predicting RAI-R highlights their significance in risk stratification.FAPI-based radiotracers have also shown potential in predicting and assessing RAI-R, with higher detection rates in specific metastatic sites like lymph nodes and the liver compared to 18 F-FDG PET/CT.This demonstrates their value as a complementary tool in evaluating refractory disease.Furthermore, RGD-based radiotracers have shown diagnostic accuracy in patients with RAI-R-differentiated thyroid cancer (DTC), with their sensitivity and specificity indicating their potential role in predicting and confirming RAI-R, particularly when compared to 18 F-FDG PET/CT. 18F-TFB is proving to be a promising PET tracer for noninvasive NIS imaging in DTC.Its ability to mimic iodide transport and provide diagnostic potential for detecting cervical lymph node metastases offers advantages over traditional scintigraphy methods.The development of targeted radionuclide therapies based on these tracers shows promise in advancing the management of refractory disease.Future research should focus on larger clinical trials, the standardization of imaging protocols, and head-to-head comparisons to establish the most effective and reliable tracers for specific clinical scenarios.
Several limitations should be acknowledged in this study.Firstly, the scope of the available literature concerning the tracers and indications under review is constrained by a limited number of studies and the limited number of inclusion of patients within these studies.Secondly, despite efforts to comprehensively review the English literature, it is possible that some relevant studies may have been missed.Moreover, the heterogeneity observed within the included studies poses a significant challenge.The variability in patient populations, study designs, imaging protocols, and outcome measures across different studies hinders the possibility of performing a meta-analysis and thus limits the establishment of definitive conclusions.
In conclusion, the use of various radiotracers in differentiated thyroid cancer is a rapidly evolving field with promising potential for improving diagnostic accuracy, patient stratification, and treatment selection.The current evidence underscores the preferential utility of select tracers.Notably, 18 F-TFB demonstrates promise in enhancing imaging resolution for DTC staging.Conversely, in the context of advanced potentially dedifferentiated DTC, tracers targeting FAP display encouraging preliminary efficacy.PSMA and RGD, in contrast, show a comparatively disappointing outcome.Hence, for future research, the authors recommend investigating FAP-targeting tracers in the advanced setting and 18 F-TFB for staging DTC, rather than further investigating PSMA and RGD.  6Ga-DOTA.SA.FAPi can detect lymph nodal, liver, bowel, and brain metastases better than 18 F-FDG in patients with RAI-R DTC.
Lymph node metastases of DTC 18 F-AIF-NOTA-PRGD2 FDG > RGD [33] No correlation was found between the uptake of 18 F-AIF-NOTA-PRGD2 and 18F-FDG, which may suggest the two tracers provide complementary information in DTC lesions.

Table 2 .
Detection Rate of Different Tracers for Thyroid Cancer Indications.