Evaluation of 18F-AlF-NOTA-octreotide for imaging neuroendocrine neoplasms: comparison with 68Ga-DOTATATE PET/CT

Objective To evaluate the diagnostic efficacy of 18F-AlF-NOTA-octreotide (18F-OC) PET/CT compared with that of 68Ga-DOTATATE PET/CT. Materials and methods Twenty patients (mean age: 52.65 years, range: 24–70 years) with biopsy-proven neuroendocrine neoplasms (NENs) were enrolled in this prospective study. We compared the biodistribution profiles in normal organs based on the maximum standard uptake value (SUVmax) and mean standard uptake value (SUVmean), and uptake in NEN lesions by measuring the SUVmax on 18F-OC and 68Ga-DOTATATE PET/CT images. The tumor-to-liver ratio (TLR) and tumor-to-spleen ratio were calculated by dividing the SUVmax of different tumor lesions by the SUVmean of the liver and spleen, respectively. The Wilcoxon signed-rank test was used to compare nonparametric data. Data were expressed as the median (interquartile range). Results In most organs, there were no significant differences in the biodistribution of 68Ga-DOTATATE and 18F-OC. 18F-OC had significantly lower uptake in the salivary glands and liver than 68Ga-DOTATATE. 18F-OC detected more lesions than 68Ga-DOTATATE. The uptake of 18F-OC in the tumors was higher in most patients, but the difference was not statistically significant relative to that of 68Ga-DOTATATE. However, the TLRs of 18F-OC were higher in most patients, including for lesions in the liver (p = 0.02) and lymph nodes (p = 0.02). Conclusion Relative to 68Ga-DOTATATE, 18F-OC possesses favorable characteristics with similar image quality and satisfactory NEN lesion detection rates, especially in the liver due to its low background uptake. 18F-OC therefore offers a promising clinical alternative for 68Ga-DOTATATE. Supplementary Information The online version contains supplementary material available at 10.1186/s13550-021-00797-4.


Introduction
Neuroendocrine neoplasms (NENs) are a relatively rare and highly heterogeneous tumor derived from neuroendocrine cells. The incidence and prevalence of NENs have increased steadily over the past 40 years, with increasing awareness and emergence of better diagnostic tools [1]. This has been accompanied by a concomitant increase in the rate of NEN distant metastases, which negatively affects NEN treatment and survival [2]. Thus, effective NEN monitoring using sensitive imaging approaches is needed to detect progression and adapt treatment strategies.
NENs commonly express somatostatin receptors (SSTRs), making them amenable to molecular imaging with radionuclide-coupled somatostatin analogs as a diagnostic tool [3]. Currently, 68 Ga-labeled somatostatin analogs (SSAs) for positron emission tomography/computed tomography (PET/CT) have been used in routine clinical practice [4,5]. Relative to single-photon emission computed tomography (SPECT), PET has a higher spatial resolution, shorter imaging times, lower radiation exposure, and better lesion detection [6,7]. Thus, PET scanning using 68 Ga-labeled SSAs is critical for tumor detection rate, staging and restaging and post-therapy follow-up [4]. However, the use of 68 Ga-labeled PET is limited by the high cost of 68 Ge/ 68 Ga generators [8] and the relatively short half-life of 68 Ga (68 min). 18 F-labeled ( 18 F half-life: 106.9 min) SSAs have high tumor-to-background ratio (TBR) for NEN lesions; thus, these probes may be used as an alternative in NEN imaging and also allow for longer transport times [9,10].
In recent years, there has been increased research on 18 F-labeled agents [10][11][12]. 18 F-AlF-NOTA-octreotide ( 18 F-OC) exhibits satisfactory biodistribution and dosimetry profiles with a high NEN lesion detection rate [13]. A comparison of the imaging parameters of 18 F-OC and 68 Ga-DOTATATE for NENs in a small number of patients found that 18 F-OC has excellent dynamics and imaging characteristics [14]. Here, we assessed the clinical applicability and efficacy of 18 F-OC relative to those of 68 Ga-DOTATATE in a larger group of patients.

Patients and study design
The research was approved by the institutional ethics review committee of Xiangya Hospital, Central South University for research purposes only (No. 20181001). All study participants gave written informed consent before the start of the study. Patients with clinically confirmed NENs were prospectively recruited into the study. Participants received an intravenous injection of 18 F-OC and 68 Ga-DOTATATE for PET/CT within 8 days (range: 1-8 days), except patients No. 1 (interval time: approximately 147 days without any treatment) and No. 15 (interval time: approximately 279 days without peptide receptor-radionuclide therapy (PRRT)). 68 Ga-DOTATATE was synthesized using the acetone method on a fully automated Modular Lab system (Eckert & Ziegler, Germany), and quality control was performed as previously described [15]. The radiochemical purity of 68 Ga-DOTATATE was > 90%. 18 F-OC was produced as previously described [16] and under good manufacturing practice guidelines.

PET/CT image acquisition
The study was carried out with a General Electric PET/ CT scanner (Discovery 690 Elite, General Electric Health care, Waukesha, Wis). 18 F-OC PET/CT imaging was performed 60 min after the radiotracer was intravenously (IV) injected at a dose of 3.7-4.44 MBq (0.1-0.12 mCi) per kilogram of body weight. 68 Ga-DOTATATE imaging was performed 50 min after an injection with a total activity of 194.4 ± 37.9 MBq. First, a low-dose CT scan (120 kV; automatic mAs; pitch, 1:1; slice thickness, 3.75 mm; matrix, 512 × 512) was performed from the head to mid-thigh for anatomical localization and attenuation correction. Next, PET scanning was performed, with 2 min per bed position. Finally, images were reconstructed using the 3-dimensional ordered-subsets expectation maximization algorithm with 2 iterations and 23 subsets.

Image analysis
Regions of interest (ROIs) were drawn on fused PET/CT images on a dedicated nuclear medicine AW 4.6 workstation (General Electric Healthcare) to obtain standardized uptake values (SUVs). 18 F-OC and 68 Ga-DOTATATE images were independently assessed by 2 experienced nuclear medicine physicians who were blinded to the patients and their medical information. The ROIs for measuring the maximum standard uptake value (SUV max ) and mean standard uptake value (SUV mean ) in normal organs and tissues and the ROIs for measuring the SUV max of NEN lesions were drawn on serial images. The mean SUV max and SUV mean in the reference organs were evaluated by placing 3 consecutive ROIs (including the area with the highest uptake and that on the upper and lower slices based on visual assessment) inside the organ of interest, including pituitary, cerebral cortex, adrenal gland, uncinate process of the pancreas (PU), pancreas (except the PU), stomach, spleen, thyroid, salivary glands, liver, bone, renal parenchyma, small intestine, uterus (female), prostate (male), colon, lung, fat, myocardium, muscle, bladder wall, and blood pool, on both scans. Candidate lesions with activities greater than the physiologic uptake in the involved organs were considered lesions. These lesions were divided into 5 regions or groups: primary tumor, liver metastases, bone metastases, lymph node metastases, and metastases in other organs (lung, muscle, stomach, rectum, peritoneum, soft tissue, and thyroid). For patients with multiple lesions, at most 5 lesions with the highest uptake per organ were included in the uptake analysis. The tumor-to-liver ratio (TLR) and tumor-to-spleen ratio (TSR) were calculated by dividing the SUV max of different tumor lesions by the SUV mean of the liver and spleen in each patients, respectively. All ratios on corresponding 18 F-OC and 68 Ga-DOTATATE scans were computed from the same layer on the 2 scans. All discrepant lesions between the images of the 2 radiotracers were identified by other imaging or patient follow-up (computed tomography (CT), magnetic resonance imaging (MRI), and PET/CT) and then classified as true-or false-positive findings.

Statistical analysis
Data analysis was performed using GraphPad Prism 6 (Version 6.01, 2012). Data are expressed as the median (interquartile range). Nonparametric data were compared using the Wilcoxon signed-rank test. P < 0.05 indicates statistical significance.

Results
Twenty patients were prospectively enrolled in the study, and their clinical characteristics are summarized in Table 1. No patients received PRRT treatment between 68 Ga-DOTATATE and 18 F-OC PET/CT scans. Both radiotracers were tolerated well by all patients, and no adverse events were reported. The physiological uptake of 68 Ga-DOTATATE and 18 F-OC is shown in Fig. 1. 68 Ga-DOTATATE and 18 F-OC PET/CT scans were compared at the lesion and region levels and based on SUV.

Biodistribution of 68 Ga-DOTATATE and 18 F-OC
Similar to that of 68 Ga-DOTATATE, the highest SUV max values for 18 F-OC were recorded in the spleen, adrenal gland, renal parenchyma, pituitary gland, liver, and PU.
Lower SUV max and SUV mean values were observed in the salivary glands, myocardium, bone, lung muscle, fat, and cerebral cortex. In most organs, the biodistribution of 68 Ga-DOTATATE was not significantly different from that of 18 F-OC. Relative to 68 Ga-DOTATATE, 18 F-OC had significantly lower uptake in organs such as the salivary glands, liver, pancreas, bone, renal parenchyma, and prostate ( Fig. 1). 68 Ga-DOTATATE and 18 Table 2 shows the discordant lesions examined by 68 Ga-DOTATATE and 18 F-OC PET/CT.

Comparison of tumor detection rates between
In the region-based comparison, 9 patients had primary tumors on both 18 F-OC and 68 Ga-DOTATATE images. In addition, there were 4 patients staged with unknown primary lesions. Sixteen patients had metastases on 68 Ga-DOTATATE PET/CT, and 17 patients had metastases on 18 F-OC PET/CT. 18 F-OC demonstrated a higher ability to detect liver lesions (Fig. 2). In 11 patients with liver metastases, 100% (11/11) and 90.9% (10/11) of patients showed liver metastases on 18 F-OC and 68 Ga-DOTATATE scans, respectively. 18 F-OC also detected peritoneal lesions more effectively than 68 Ga-DOTA-TATE in 1 patient (No. 9).
In the lesion-based examination, 68 Ga-DOTATATE and 18 (Table 2). Both 18 F-OC and 68 Ga-DOTATATE had lesions that could not be detected by another imaging agent (Fig. 3). 18 F-OC detected 28 lesions (23 in the liver, 2 in the lymph node, and 3 in the There was a difference of 10 liver metastases detected by the 2 radiotracers in patient No. 14 ( Fig. 2), which  19 (a, b) and No. 20 (c, d). The 18 F-OC fusion image (b) found an increased uptake in a retroperitoneal lymph node, while the uptake of this lymph node was not significantly increased on 68 Ga-DOTATATE (a) image. However, in another patient, the 18 F-OC fusion image (d) shows that the uptake in one retroperitoneal lesion was not obvious, while the uptake of 68 Ga-DOTATAE was significant (c) were confirmed as true lesions by follow-up CT and MR. Additionally, 18 F-OC detected 3 peritoneal lesions in patient No. 9. Regarding lymph node lesions, both 18 F-OC and 68 Ga-DOTATATE detected 1 lesion that was not clearly detected by the other imaging agent. In addition, 18 F-OC and 68 Ga-DOTATATE PET/CT had comparable effectiveness in detecting primary tumors and bone metastases.
Lesion uptake analysis found that 18 F-OC uptake was slightly higher than 68 Ga-DOTATATE uptake in primary tumors and metastases, but there were no significant differences (primary tumor: 25.01 (16. Fig. S1). Furthermore, in liver and lymph node lesions, the 18 F-OC TLR was higher than that with 68 Ga-DOTATATE (p = 0.02, Fig. 4). However, the 18 F-OC TSR was not significantly higher than that of 68 Ga-DOTATATE for primary tumor or metastases (Fig. 4).
In our study, we found that despite physiological uptake in the PU (mentioned above), three cases of nodules with abnormal density or signal in the PU on CT or MRI showed abnormal uptake in the PU on 68 Ga-DOTA-TATE and 18

Discussion
Here, we prospectively assessed the performance of 18 F-OC PET/CT relative to 68 Ga-DOTATATE PET/CT in 20 NEN patients. The 18 F-OC had a favorable biodistribution profile and was not inferior to 68 Ga-DOTATATE in tumor uptake, TLR and TSR.
Our data showed that the 18 F-OC distribution in organs was similar to that of 68 Ga-DOTATATE. 18 F-OC accumulation was very high in the spleen, which was similar to that of 68 Ga-labeled DOTA-SSAs. Because both radiotracers were mainly excreted by the urinary system, higher uptake was seen in the kidneys. However, the overall uptake of 18 F-OC in organs was lower than that of 68 Ga-DOTATATE, especially in the liver, where the background 68 Ga-DOTATATE uptake was 1.5 times greater than that of 18 F-OC. We found that the salivary glands showed visible differences between the 2 radiotracers, which was consistent with past findings that 68 Ga-DOTATATE uptake by salivary glands was foursixfold higher than that of 18 F-OC, mainly because of different radiotracer clearance times [14].
Because of high physiological uptake due to high SSTR2 expression in the PU and artifacts caused by respiratory movement, focal pancreatic lesions and lesions around the head of the pancreas may be obscured. Here, we found that both 18 F-OC and 68 Ga-DOTATATE had high uptake nodules in the PU, and other imaging examinations (CT or MRI) showed changes in the shape, signal or density of these nodules (Additional file 2: Fig. S2). Other imaging agents based on 68 Ga-labeled radionuclides also demonstrated high sensitivity and specificity Fig. 4 Bar chart representing the maximum standardized uptake value (SUV max, a), tumor-to-liver ratio (TLR, b) and tumor-to-spleen ratio (TSR, c) of 18 F-OC. TLR (b) and TSR (c) were calculated by dividing the SUV max of tumor lesions by the patient-specific SUV mean of the liver and spleen, respectively. The TLRs for lesions in the liver and lymph nodes were significantly higher with 18 F-OC (p = 0.02 and p = 0.02, respectively). All other SUV max , TLR and TLR calculations did not show significant differences for detecting lesions (93.6% and 90%, respectively) in the PU [17]. We considered that results of a previous study [17] and ours could indicate SSA-PET, combined with morphological information (CT or MRI), especially if performed with enhanced CT or MRI, will improve the accuracy of lesions in the PU. But our number of cases was relatively small (n = 3). Thus, larger studies are needed to confirm these findings. 18 F-OC and 68 Ga-DOTATATE were highly sensitive in detecting lesions, and there were no differences in their overall diagnostic efficacy. Relative to 68 Ga-DOTATATE, 18 F-OC can detect lesions better (177 vs. 152), especially lesions in the liver (116 vs. 93), probably due to the lower background level of 18 F-OC uptake in the liver. This finding is of great clinical significance, as it may affect treatment methods. For example, in patient No. 3, liver lesions were detected with 18 F-OC but not 68 Ga-DOTATATE. In patient No. 10, only one lesion was detected in the left lobe with 68 Ga-DOTATATE, while 18 F-OC detected another lesion in the right lobe of the liver, which was confirmed to be NEN metastases through pathology. These data are consistent with findings by Pauwels et al. [14] that 18 F-OC detects more liver lesions.
Our data did not uncover differences between 68 Ga-DOTATATE and 18 F-OC in the detection of bone lesions (8 vs. 8). However, Pauwels et al. [14] found that 18 F-OC detects more bone lesions. The differences between the 2 studies may be due to the small number of bone lesions in our study. Regarding lymph node lesions, both imaging radiotracers detected unique lesions. Additionally, 18 F-OC detected 3 relatively small peritoneal metastases (diameter: < 5 mm) in patient No. 9, which were missed by 68 Ga-DOTATATE. This is attributable to 18 F being a typical short-distance positron emitter with better spatial resolution [18], which may be better suited for detecting small lesions. Thus, the capacity of 18 F-OC to detect lesions is similar to that of 68 Ga-DOTATATE, and 18 F-OC may detect liver lesions more efficiently.
In this study, the SUV max of 18 F-OC was higher than that of 68 Ga-DOTATATE, but the difference was not statistically significant. Interestingly, relative to 68 Ga-DOTATATE, 18 F-OC had a better target-to-background ratio. In this study, using liver and spleen for background comparisons, we found the 18 F-OC TLRs for lesions in the liver and lymph node were significantly higher than those of 68 Ga-DOTATATE, probably due to low liver background with 18 F-OC. However, this finding differs from the results from Pauwels et al. [14] that the 18 F-OC SUV max for all lesions were significantly lower than those of 68 Ga-DOTATATE, but there was no difference in TBR, which may be attributable to the small sample size. We also found that some patients exhibited higher 68 Ga-DOTATATE uptake in lesions while others had higher 18 F-OC uptake, and even within the same patient, some lesions had higher 68 Ga-DOTATATE uptake while others had greater 18 F-OC uptake; this is probably because of NEN heterogeneity [19]. The reason for the difference between the two radiotracers still needs further study.
Taken together, we found that 18 F-OC had similar characteristics to 68 Ga-DOTATATE in terms of physiological distribution, lesion detection, and lesion uptake. However, 18 F-OC was relatively better in detecting liver lesions than 68 Ga-DOTATATE. The two radiotracers had significantly difference TLRs, which is an important parameter for lesion detection.

Limitations
The most significant limitation of this study was the lack of pathological confirmation of most lesions, which was not performed due to the ethical implications of pathologically examining all patient lesions. Thus, all lesions found with 18 F-OC and 68 Ga-DOTATATE were confirmed using alternative imaging approaches such as 18 F-FDG PET, CT, or MRI. In addition, due to the small size of the study group and the small number of patients with higher-grade NENs, we could not evaluate the correlation between uptake and tumor grade. Future studies will involve a larger sample size.

Conclusion
Overall, 18 F-OC shows a favorable biodistribution, in which the uptake in various organs is similar to or even lower than that of 68 Ga-DOTATATE. 18 F-OC can detect liver lesions better than 68 Ga-DOTATATE, with a better tumor-to-liver ratio. However, both 18 F-OC and 68 Ga-DOTATATE have similar detection rates for lesions in other organs. In general, 18 F-OC has great potential as an alternative to 68 Ga-DOTATATE in the absence of a 68 Ge/ 68 Ga generator. In the future, more patients are needed for comparisons between 68 Ga-DOTATATE and 18 F-OC to verify the value of 18 F-OC in clinical applications.