
==== Front
EJNMMI Rep
EJNMMI Rep
EJNMMI Reports
3005-074X
Springer International Publishing Cham

39245688
217
10.1186/s41824-024-00217-5
Original Article
[18F]AlF-PSMA-11 PET in diagnosing prostate cancer: a head-to-head comparison with [68Ga]Ga-PSMA-11 PET and an exploration of dual-phase scanning
http://orcid.org/0000-0003-4135-2275
Li Xiao lixiao_nm@smmu.edu.cn

12
Yu Mingming 3
Yang Jian 4
Li Danni 1
Li Rou 1
Mao Juanli 1
Zuo Changjing 1
Liang Zeying 4
Li Qiang rmliqiang@nbu.edu.cn

3
Cheng Chao 13501925757@163.com

1
1 https://ror.org/02bjs0p66 grid.411525.6 0000 0004 0369 1599 Department of Nuclear Medicine, Shanghai Changhai Hospital, Shanghai, 204333 China
2 grid.9227.e 0000000119573309 Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, 201800 China
3 https://ror.org/03et85d35 grid.203507.3 0000 0000 8950 5267 Department of Radiology, The Affiliated People’s Hospital of Ningbo University, Ningbo, 315040 Zhejiang China
4 https://ror.org/006teas31 grid.39436.3b 0000 0001 2323 5732 School of Medicine, Shanghai University, Shanghai, 200444 China
9 9 2024
9 9 2024
12 2024
8 1 286 5 2024
9 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Purpose

To evaluate the physiological distribution and tumour detection ability of [18F]AlF-PSMA-11 positron emission tomography (PET) dual-phase scans in patients with prostate cancer (PCa).

Methods

As a retrospective study, clinical and PET data of PCa patients who underwent dual-phase [18F]AlF-PSMA-11 PET of routine scan (45–50 min) and delayed scan (120 min) from November 2020 to June 2021 were collected, and physiological and pathological regions of interest were quantified to determine the time-dependent maximum standardized uptake value (SUVmax) of [18F]AlF-PSMA-11. Part of the above subjects who underwent [68Ga]Ga-PSMA-11 PET in the following 6 months were included in a head-to-head comparison. The difference with a p-value < 0.05 was defined as statistical significance. Diagnosis accuracy of primary and metastatic lesions was measured referring to the surgical findings, pathology, and follow-up imaging.

Results

[68Ga]Ga-PSMA-11 and [18F]AlF-PSMA-11 were of the comparable uptake in glands in head, but the latter was of a significant lower distribution in liver and spleen. For the 25 patients initially diagnosed with prostate cancer and 3 patients with biochemical recurrence after radical surgery, the SUVmax of the primary lesions, lacrimal glands, parotid glands and submandibular glands was higher at 120 min compared to that at 45–50 min, but not a significant difference. SUVmax of the liver, spleen and bladder decreased significantly at 120 min, but the bladder SUVmax remained higher than that of primary lesions. SUVmax of the kidneys and centrum was the same in dual-phase scans. For the 31 primary lesions detected in [18F]AlF-PSMA-11 PET, both the SUVmax of the two phases kept the positive correlation with PSA, Gleason score and initial risk stratification. For the 39 distant metastatic lesions, 94.87% accuracy of routine scan and 100% accuracy of delayed scan were acquired, and 7.14% patients (2/28) benefited from the dual-phase [18F]AlF-PSMA-11 scans that revealed novel information on metastatic lesions compared to the routine scan.

Conclusion

[18F]AlF-PSMA-11 PET expanded the time window and further decreased metabolic background of [68Ga]Ga-PSMA-11 PET. The dual-phase scan of [18F]AlF-PSMA-11 PET can benefit prostate cancer diagnosis via providing more PSMA-specific information.

Keywords

[18F]AlF-PSMA-11
[68Ga]Ga-PSMA-11
PSMA PET
Dual-phase scans
Prostate Cancer
the First Affiliated Hospital of Naval Medical University (Shanghai Changhai Hospital) “Guhai Plan in the 14th Five-Year Plan period”GH145-22 and GH145XKQ-03 Zuo Changjing Shanghai Hospital Development CenterSHDC1202310 Zuo Changjing issue-copyright-statement© Springer Nature Switzerland AG 2024
==== Body
pmcIntroduction

Prostate cancer (PCa) is one of the most common malignancies in men worldwide and the second leading cause of cancer-related death in males (Siegel et al. 2023). Accurate staging and localization is essential for selecting appropriate treatment strategies, such as active surveillance, radical prostatectomy, radiation therapy, hormone therapy and watchful waiting (Mottet et al. 2021). Currently recommended imaging staging methods for PCa include magnetic resonance imaging (MRI), computed tomography (CT) and bone scintigraphy. MRI is mainly used for evaluating the extent of primary tumour infiltration and pelvic lymph node metastasis due to its excellent soft tissue contrast (Williams et al. 2022). CT and bone scintigraphy are used to assess distant metastasis, but they have low sensitivity and may result in missed diagnoses (Maurer et al. 2016; Zhao and Ji 2022). As a whole-body functional imaging modality, positron emission tomography (PET) has been widely used in the staging of malignant tumours. In the majority of PCa cases, prostate-specific membrane antigen (PSMA) is an overexpressed cell surface transmembrane protein. Since PSMA exhibits high affinity with PSMA-targeting molecular probes, PSMA ligand-targeted PET imaging has significant advantages in the diagnosis, staging, follow-up and prognostic evaluation of PCa (Hofman et al. 2020; Koerber et al. 2017).

Various PSMA-targeted PET imaging agents have been developed, including [68Ga]Ga-PSMA-11 (Koerber et al. 2017; Uprimny et al. 2017), [18F]F-PSMA-1007 (Kuten et al. 2020; Rahbar et al. 2018) and [18F]F-DCFPyL (Morris et al. 2021; Rowe et al. 2022). Among them, [68Ga]Ga-PSMA-11 is widely accepted in clinical practice due to its convenient preparation and availability of the radionuclide (Koerber et al. 2017). However, the shorter half-life and larger positron emission energy of Ga-68 compared to F-18 may affect diagnostic accuracy (Dietlein et al. 2015). [18F]AlF-labeled PSMA-HBED-CC (hereafter, [18F]AlF-PSMA-11), a novel PSMA-targeted PET imaging agent and an alternative to [68Ga]Ga-PSMA-11, replaces [68Ga]Ga with [18F]AlF because the radionuclide F-18 has a more suitable half-life for PET applications without altering the framework of the PSMA-HBED-CC precursor. Although [18F]AlF-PSMA-11 has been deemed an attractive alternative to [68Ga]Ga-PSMA-11 for PCa imaging, its advantages and clinical applications have been rarely studied (De Man et al. 2022; van Leeuwen and Emmett 2022). This study aims to understand the tracer metabolism and physiological distribution of [18F]AlF-PSMA-11 via a head-to-head comparison with [68Ga]Ga-PSMA-11 PET, as well as to investigate the application of [18F]AlF-PSMA-11 PET in diagnosing PCa, especially the added value of dual-phase imaging in PCa management.

Materials and methods

Study design and patient population

A retrospective analysis of PCa patients who underwent [18F]AlF-PSMA-11 PET imaging at Changhai hospital from November 2020 to June 2021 was conducted. The study was approved by the ethics committee of Changhai hospital (Approval No. CHEC2019-090). The data are anonymous and retrospective, so the requirement for informed consent was waived. Inclusion criteria were as follows: (a) histologically or surgically confirmed PCa; (b) availability of Gleason score and PSA results within 2 weeks. For the above patients with a [68Ga]Ga-PSMA-11 PET performed within 6 months, the clinical data were further included in the head-to-head comparison with [18F]AlF-PSMA-11 PET.

Imaging protocol

[18F]AlF-PSMA-11 was prepared in-house according to our previously reported optimised protocol with a labeling kit of Al-PSMA-11 (Kersemans et al. 2018; Li et al. 2022). Patients received intravenous injection of [18F]AlF-PSMA-11 at a dose of 1.85 MBq/kg. After injection, the patients were instructed to drink water and rest quietly for 45–50 min, followed by voiding and lying supine on the PET/CT scanning bed. This study defined imaging at 45–50 min as routine imaging, and imaging at 120 min as delayed imaging. Imaging acquisition was performed using a Siemens Biograph 64 PET/CT scanner. Patients maintained calm breathing, and the scanning range extended from the head to the mid-thigh. A whole-body CT scan was performed first, with a current of 170 mA, a voltage of 120 kV and a slice thickness of 3 mm. Subsequently, PET scanning was performed to acquire 5–6 bed positions, including 1–2 abdominal positions and 1 head position, with a duration of 3 min per bed position. PET images were corrected for CT attenuation and reconstructed using the TrueD system on a post-processing workstation to generate PET/CT fusion images in transverse, coronal and sagittal planes and maximum intensity projection (MIP).

Patients drank water and rested quietly, and all but seven patients were then scanned with a PET/CT again at 120 min. For better soft tissue contrast, the other seven patients underwent a delayed scan at 120 min with an integrated PET/MR scanner (Biograph mMR, Siemens Healthcare) that combines PET and 3.0-T MRI scanners. After a fast and simple MRI scout imaging sequence, a whole-body PET scan (3 min/bed position) was conducted for 5–6 bed positions. MRI was concurrently conducted using the following protocol: T1-weighted 3D volumetric interpolated breath-hold examination with Dixon fat saturation (3D, transversal, TR 4.07 ms, TE 1.28 ms, flip angle 12°, 72 slices, slice thickness 3 mm, field of view 400 × 400, voxel size 1.3 × 1.3 × 3.0 mm3), and T2W-BLADE (transversal, TR 3000 ms, TE 89 ms, flip angle 90°, 33 slices, slice thickness 6 mm, field of view 400 × 400, voxel size 1.3 × 1.3 × 6.0 mm3). PET data were reconstructed using high-definition PET (3 iterations, 21 subsets; matrix 172 × 172, voxel size 2.3 × 2.3 × 5.0 mm3). The Dixon sequence was used to derive MRI-based attenuation correction.

[68Ga]Ga-PSMA-11 PET/CT was performed following the same procedure with the routine scan of [18F]AlF-PSMA-11 PET/CT.

Image analysis and interpretation

All images were independently reviewed by two nuclear medicine physicians with more than 8 years of diagnostic experience. The maximum standardised uptake value (SUVmax) within the region of interest (ROI) was independently delineated on two sets of PET images. Conversion factors for SUVmax between PET/CT and PET/MR were calculated using a water phantom in advance of quantitative investigation, and the results showed that the PET counts were equivalent between the two modalities. For the precise analysis, our previous report on the two scanners has confirmed the consistency of quantification (Zhang et al. 2022). All subjects were followed up until December 2023, and the diagnosis accuracy of primary and metastatic lesions was measured referred to the surgical findings, pathology, and follow-up imaging examinations.

Statistical analysis

The data were analyzed using IBM SPSS 21.0 software. Normally distributed continuous variables were presented as mean ± standard deviation (SD). Graphs were charted with Origin 2024. Independent samples t-test was used for comparing quantitative data. A p-value < 0.05 was considered to indicate statistical significance.

Results

A total of 28 PCa patients were retrospectively recruited, including 25 patients with initial PCa diagnosis and 3 patients with postoperative biochemical recurrence. Detailed clinical characteristics and pathological results are summarized in Table 1. Among them, 4 patients received a follow-up [68Ga]Ga-PSMA-11 PET/CT within 6 months. For the head-to-head comparison of [18F]AlF-PSMA-11 PET and [68Ga]Ga-PSMA-11 PET, there were comparable tracer uptakes in those glands in head (Fig. 1a-c), however, a significant lower tracer uptake was observed in [18F]AlF-PSMA-11 PET of liver and spleen (Fig. 1d-e), when compared with [68Ga]Ga-PSMA-11 PET. The confounding factors, such as specific activity and radiochemical purity of PSMA-11-derived radiopharmaceuticals, were strictly controlled, therefore, pharmacokinetics of [18F]AlF-PSMA-11 were the only factor in determining the clearer background of metabolic organs in PET imaging. Kidneys were of a similar SUVmax in the two scans (Fig. 1f).

Table 1 Clinical and pathological characteristics of PCa patients who underwent [18F]AlF-PSMA-11 PET

Characteristic and Pathology	Value or Number (Percentage, %)	
Age (mean ± SD)	(67.7 ± 7.1) y	
PSA (ng/mL)		
 ≤ 10	11 (39.3)	
 > 10	17 (60.7)	
Gleason score		
 ≤ 7	13 (46.4)	
 > 7	15 (53.6)	
Distant metastasis		
 M0	19 (67.9)	
 M1	9 (32.1)	
Initial risk stratification		
 Intermediate risk	11 (39.3)	
 High risk	17 (60.7)	

Fig. 1 Comparison of tracer uptake between [18F]AlF-PSMA-11 PET and [68Ga]Ga-PSMA-11 PET in glands in head (a, b and c) and metabolic organs (d, e and f). The representative [18F]AlF-PSMA-11 PET images were of a 65-year-old man with prostate cancer, GS 4 + 5 and serum PSA value 45.19 ng/mL, and the [68Ga]Ga-PSMA-11 PET was acquired at 4 months later

Table 2 presents the quantitative data of tissues or organs with obvious tracer uptake. In the primary lesions of PCa patients, a comparable quantification was acquired at 45–50 min and 120 min. For the lacrimal glands, parotid glands and submandibular glands, there was a rising trend in SUVmax at 120 min compared to that at 45–50 min, but the difference was not significant, pointing to the PSMA-specific [18F]AlF-PSMA-11 uptake by these tissues and the extended time window of PSMA PET. Conversely, the liver, spleen and bladder showed a significant decrease in SUVmax at 120 min compared to that at 45–50 min, further strengthening the advantage of [18F]AlF-PSMA-11 PET with a clearer metabolic background. The diagnosis of pelvic lesions will potentially benefit from the noticeable decrease of bladder SUVmax in the delayed imaging even though the value of SUVmax remains higher than that of the lesions. Due to the continuous clearance of [18F]AlF-PSMA-11, the SUVmax of the kidneys was nearly identical in both scans. Overall, the replacement of [68Ga]Ga with [18F]AlF enabled delayed PSMA-11 PET, leading to an increased tracer uptake or maintained PSMA-specific tracer uptake.

Table 2 Quantification of whole-body distribution of [18F]AlF-PSMA-11

Location	SUVmax	t	P	
Routine Scan	Delayed Scan	
PCa*	13.54 ± 9.09	13.96 ± 11.56	-0.141	0.888	
Lacrimal gland	7.72 ± 3.57	9.69 ± 4.73	-1.651	0.105	
Parotid gland	11.70 ± 5.21	13.22 ± 6.99	-0.873	0.387	
Submandibular gland	11.62 ± 4.62	12.54 ± 6.44	-0.582	0.564	
Liver	4.20 ± 1.42	2.96 ± 1.04	3.336	0.002	
Spleen	5.56 ± 2.55	3.76 ± 1.60	2.782	0.004	
Bladder	35.33 ± 24.32	18.10 ± 13.44	3.128	0.003	
Kidney	31.57 ± 12.21	31.54 ± 16.42	0.006	0.995	
Bone (Centrum-L5)	3.43 ± 1.26	3.70 ± 1.78	-0.637	0.527	
*SUVmax of primary lesions was measured in 25 non-surgical patients, and in cases with multiple primary lesions, the average value of the lesions was obtained

In evaluating the 25 non-surgically treated patients with [18F]AlF-PSMA-11 PET, 31 primary lesions in the prostate were detected by routine imaging at 45–50 min and then confirmed by delayed imaging at 120 min, accordingly, the ratio of target (primary lesion) to background (liver) increased as shown in Fig. 2a (SUVmax) and Fig. 2b (SUVmean). Unlike the unaltered number of lesions, the range of primary lesions tended to expand in the delayed scanning (Fig. 2c-h), standing for a more precise mapping of PSMA-related lesions. Table 3 summarizes the difference in [18F]AlF-PSMA-11 uptake between groups divided by PSA, Gleason score or risk stratification. There were comparable values of differential diagnosis by SUVmax at 45–50 min and 120 min. For both the quantification at routine and delayed scans, SUVmax of primary PCa lesions showed a positive correlation with PSA level, Gleason score and risk stratification at both 45–50 min and 120 min, implying that PSA level, Gleason score and risk stratification continuously served as the inherent factors in determining SUVmax of primary lesions in the dual-phase scans of [18F]AlF-PSMA-11 PET.

Fig. 2 The target to background ratios of SUVmax (a) and SUVmean (b) of [18F]AlF-PSMA-11 PET of primary lesions, and images of a 63-year-old man with prostate cancer, GS 3 + 4 and serum PSA value 10.15 ng/mL. In routine imaging, performed 50 min after [18F]AlF-PSMA-11 injection, (c) PET MIP, (d) PET and (e) fused PET/CT show increased focal tracer uptake (SUVmax, 11.40) in the prostatic region (red and green arrows). In delayed imaging, performed 120 min after [18F]AlF-PSMA-11 injection, (f) PET MIP, (g) PET and (h) fused PET/MR show increased focal tracer uptake (SUVmax, 10.61) in the prostatic region (red and green arrows) and expanded tracer uptake range

Table 3 Correlation of SUVmax of primary prostate lesions with PSA, Gleason score and Risk Assessment

Characteristic and Pathology	SUVmax at 45–50 min	t	P	SUVmax at 120 min	t	P	
PSA		-2.353	0.030		-2.419	0.029	
 ≤ 10	9.74 ± 5.06			11.52 ± 5.31			
 > 10	16.44 ± 7.29			20.11 ± 7.70			
Gleason		-2.417	0.029		-2.171	0.049	
 ≤ 7	9.46 ± 4.98			9.50 ± 4.56			
 > 7	17.55 ± 8.20			17.54 ± 8.80			
Initial risk stratification		-2.614	0.021		-2.916	0.012	
 Intermediate	10.17 ± 4.92			10.32 ± 4.13			
 High risk	18.94 ± 7.56			19.03 ± 8.35			

Among the 28 cases, a total of 39 distant metastatic lesions were detected in the dual-phase [18F]AlF-PSMA-11 scan and then verified with the surgical findings, pathology, and follow-up imaging, such as MRI and [99mTc]Tc-MDP SPECT/CT. For the 39 distant metastatic lesions, 94.87% accuracy of routine scan and 100% accuracy of delayed scan were acquired, and 7.14% patients (2/28) benefited from the dual-phase [18F]AlF-PSMA-11 scans that revealed novel information on metastatic lesions compared to the routine scan.

Specifically, in a case with a negative early scan (Fig. 3a-c), a solitary bone metastasis (SUVmax, 5.94) was only revealed by the delayed imaging (Fig. 3d-f). In a follow-up [99mTc]Tc-MDP SPECT/CT scan that was performed at 15 months later, a metastasis at the same anatomy was identified (Fig. 3g). Additionally, one patient exhibited unclear findings, since pelvic lymph node involvement was observed in routine imaging, but reduced tracer uptake to a background level was observed in delayed imaging, indicating non-metastatic lymph nodes (Fig. 4). Lymph node dissection during subsequent surgery confirmed the absence of lymph node metastasis in this patient. Overall, the dual-phase imaging with [18F]AlF-PSMA-11 PET give the nuclear medicine physicians more confidence in making a diagnosis on the basis of PSMA correlation.

Fig. 3 A 56-year-old man with prostate cancer who underwent radical prostatectomy 6 months ago with a serum PSA value of 1.14 ng/mL. The patient did not receive radiation therapy or hormonal therapy after surgery. In routine imaging, performed 50 min after [18F]AlF-PSMA-11 injection, (a) PET/CT axial CT image shows mild increased bone density on the right iliac bone (red arrow), and (b) PET and (c) fused PET/CT images show no focal tracer uptake (red and green arrows) in the corresponding area. In delayed imaging, performed 120 min after [18F]AlF-PSMA-11 injection, (d) PET/MR-T1WI image shows mild restricted signal on the right iliac bone (red arrow), and (e) PET and (f) fused PET/MR images show tracer uptake (SUVmax, 5.94) on the right iliac bone (red and green arrows). (g) shows the high uptake of 99mTc-MDP in the same focol location in a follow-up SPECT/CT scan performed at 15 months later

Fig. 4 A 63-year-old man with prostate cancer, GS 4 + 4 and serum PSA value of 11.68 ng/mL. In routine imaging, performed 50 min after [18F]AlF-PSMA-11 injection, (a) axial PET/CT, (b) PET and (c) fused PET/CT images show tracer uptake (SUVmax, 5.3) on the right pelvic wall (red arrows). In delayed imaging, performed 120 min after [18F]AlF-PSMA-11 injection, (d) PET/MR-T1WI, (e) PET and (f) fused PET/MR images show no tracer uptake in the lymph nodes (red arrows). The final surgical pathology confirms the absence of lymph node metastasis in this patient

Discussion

Due to its pathological over-expression in PCa patients, PSMA has become an ideal target for the diagnosis and treatment of PCa (Farolfi et al. 2021; Lütje et al. 2015). [18F]AlF-PSMA-11, a novel PSMA imaging agent, has the same molecular precursor as [68Ga]Ga-PSMA-11 but a longer half-life and lower electron emission energy due to the replacement of the radioactive isotope with F-18, resulting in a higher PSMA-positive lesion detection rate compared to [68Ga]Ga-PSMA-11 (De Man et al. 2022). In this study, the physiological distribution, tumour detection capability and delayed imaging of [18F]AlF-PSMA-11 in PCa patients were demonstrated through dual-phase PET imaging. Although both [68Ga]Ga-PSMA-11 and [18F]AlF-PSMA-11 were PSMA-11-derived radiopharmaceuticals, the chemical formula of [18F]AlF-PSMA-11 was more complex, furthermore, the difference of electric charge of [18F][AlF]2+ and [68Ga]Ga3+ potentially affected the pharmacokinetics of tracers. Referring to the head-to-head comparison, PSMA-specificity was not influenced, while replacing [68Ga]Ga3+ with [18F][AlF]2+ minimized the metabolic burden of liver and spleen.

Good and stable target uptake is an important prerequisite for the application of targeted molecular probes. The results of this study showed good imaging of [18F]AlF-PSMA-11 in primary prostate lesions, lacrimal glands and salivary glands, with high uptake still observed in the delayed imaging performed at 120 min, indicating a favourable and stable biological distribution of [18F]AlF-PSMA-11 in target organs. Notably, the SUVmax of the liver and spleen significantly decreased in the delayed imaging, which is advantageous for the detection of liver metastases. In contrast, another F-18 labelled PSMA imaging agent, [18F]F-PSMA-1007, may not be suitable for the detection of liver metastases due to its hepatic clearance (Rahbar et al. 2018). Maintaining the metabolic characteristics of [68Ga]Ga-PSMA-11, [18F]AlF-PSMA-11 is also excreted through the kidneys, resulting in high tracer accumulation in the bladder during delayed imaging. Afshar et al. demonstrated that by prolonging the scan time to 3 h and administering a diuretic to reduce the bladder tracer concentration, more occult lesions around the bladder could be detected in delayed [68Ga]Ga-PSMA-11 imaging (Afshar-Oromieh et al. 2017). However, further research is needed to determine whether an increased detection rate of lesions around the bladder can be achieved by adopting a longer delay in imaging (e.g., 4 h) without administering a diuretic for patients who have contraindications to diuretics. The longer half-life of F-18 makes it more suitable for PET imaging, allowing for higher resolution even with delayed scans.

The results of this study showed that delayed imaging with [18F]AlF-PSMA-11 can clarify the nature of lesions. In one case of biochemical recurrence after radical surgery (Fig. 3), a solitary bone metastasis was detected in the delayed imaging, and careful observation revealed slight bone abnormalities on CT and MR, which was manifested as a bone metastasis in a follow-up MDP SPECT/CT. In another case, a patient suspected of having lymph node metastasis showed significantly reduced uptake in the delayed imaging (Fig. 4), and subsequent surgery confirmed the absence of pelvic lymph node metastasis. Similar results have been reported in previous studies (Afshar-Oromieh et al. 2016, 2017; Rahbar et al. 2018; Sahlmann et al. 2016), where both the SUVmax values and target-to-background ratios of malignant lesions significantly increased with time. Such appearance may result from the ability of PSMA receptors binding to the imaging agent is directly proportional to time, whereas the imaging agent in non-target tissues is rapidly cleared over time, thereby improving the target-to-background ratio through delayed imaging. These additive PSMA-specific information resulted from the dual-phase [18F]AlF-PSMA-11 PET was hopeful to decrease the necessity of confirmatory examination, such as bone scintigraphy. Although only two cases (7.14%) in this study had changes in tumour staging based on delayed imaging, a larger sample size may reveal more missed lesions with routine imaging compared to delayed imaging with [18F]AlF-PSMA-11. Therefore, we recommend extending the scan time appropriately for [18F]AlF-PSMA-11 PET, although determining the optimal scan time still requires further expansion of sample studies.

Most literature suggests that the SUVmax of PSMA PET is positively correlated with PSA, Gleason score and risk stratification (Ergül et al. 2018; Uprimny et al. 2017). [18F]AlF-PSMA-11 maintained the PSMA-specificity of PSMA-HBED-CC, that is to say, the SUVmax of primary prostate lesions increased as the PSA, Gleason score and risk level increased, consistent with the literature. In the delayed imaging of [18F]AlF-PSMA-11 PET, we found a small number of cases exhibited diffused bone uptake, potentially resulting from F-18 being prone to deposition in the bones, especially in benign conditions such as osteogenesis, joint degeneration and old fractures. Similarly, due to de-labelling or relatively low radiochemical purity, Rauscher et al. found that [18F]F-PSMA-1007 detected more benign lesions than [68Ga]Ga-PSMA-11 (Rauscher et al. 2020). This requires diagnostic physicians to have extensive clinical experience and make comprehensive judgments based on the patient’s medical history, PSA and Gleason score.

Here, we preliminarily reported the additional value of [18F]AlF-PSMA-11, but there are certain limitations to this study. First, since this was a small-sample study, further studies with larger sample sizes are needed to validate the findings, especially the best choice of delayed scans protocol. Second, although our diagnostic physicians have extensive diagnostic experience, there could have been some false positives due to the lack of pathological confirmation for some bone metastatic lesions. Further follow-up or pathological confirmation is needed. Finally, a head-to-head comparison between [68Ga]Ga-PSMA-11 and [18F]AlF-PSMA-11 was performed on three tumour-free subjects already (Li et al. 2022), and an extensive head-to-head validation performed on four PCa patients was carried out in this study, but a further comparison focused on tumour was more meaningful in exploring the clinical advantages of [18F]AlF-PSMA-11 PET.

Conclusion

This clinical study demonstrated that [18F]AlF-PSMA-11 can bind to receptors stably and persistently, meantime, a clearer metabolic background was manifested when compared with [68Ga]Ga-PSMA-11 PET, indicating that [18F]AlF-PSMA-11 has great potential as an alternative PSMA imaging agent to [68Ga]Ga-PSMA-11 since it allows for further characterization of lesions through delayed imaging.

Acknowledgements

Not applicable.

Author contributions

Xiao Li and Chao Cheng and contributed to the study conception and design. Material preparation and experiment were performed by Xiao Li, Mingming Yu, Danni Li, Rou Li, Juanli Mao and Zeying Liang. Data collection and analysis were performed by Mingming Yu, Jian Yang and Xiao Li. The first draft of the manuscript was written by Mingming Yu and Danni Li. Changjing Zuo, Qiang Li and Xiao Li contributed to critical revision. Changjing Zuo provided the fund support.

Funding

This work was funded by the First Affiliated Hospital of Naval Medical University (Shanghai Changhai Hospital) “Guhai Plan in the 14th Five-Year Plan period” (GH145-22 and GH145XKQ-03) and Shanghai Hospital Development Center (No. SHDC12023103).

Data availability

Data are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the ethics committee of Changhai hospital (Approval No. CHEC2019-090). The data are anonymous and retrospective, so the requirement for informed consent was waived.

Consent for publication

All authors read and approved the final version of the manuscript to be published.

Competing interests

The authors declare no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xiao Li, Mingming Yu and Jian Yang contributed equally to this research.
==== Refs
References

Afshar-Oromieh A Hetzheim H Kübler W Kratochwil C Giesel FL Hope TA Radiation dosimetry of 68Ga-PSMA-11 (HBED-CC) and preliminary evaluation of optimal imaging timing Eur J Nucl Med Mol Imaging 2016 43 9 1611 1620 10.1007/s00259-016-3419-0 27260521
Afshar-Oromieh A, Hetzheim H, Kübler W, Kratochwil C, Giesel FL, Hope TA et al (2016) Radiation dosimetry of (68)Ga-PSMA-11 (HBED-CC) and preliminary evaluation of optimal imaging timing. Eur J Nucl Med Mol Imaging 43(9):1611–162027260521 10.1007/s00259-016-3419-0
Afshar-Oromieh A Sattler LP Mier W Hadaschik BA Debus J Holland-Letz T The clinical impact of additional late PET/CT imaging with 68Ga-PSMA-11 (HBED-CC) in the diagnosis of prostate Cancer J Nucl Med 2017 58 5 750 755 10.2967/jnumed.116.183483 28062595
Afshar-Oromieh A, Sattler LP, Mier W, Hadaschik BA, Debus J, Holland-Letz T et al (2017) The clinical impact of additional late PET/CT imaging with 68Ga-PSMA-11 (HBED-CC) in the diagnosis of prostate Cancer. J Nucl Med 58(5):750–75528062595 10.2967/jnumed.116.183483
De Man K Van Laeken N Schelfhout V Fendler WP Lambert B Kersemans K 18F-PSMA-11 Versus 68Ga-PSMA-11 Positron Emission Tomography/Computed tomography for staging and biochemical recurrence of prostate Cancer: a prospective double-blind Randomised Cross-over Trial Eur Urol 2022 82 5 501 509 10.1016/j.eururo.2022.05.010 35690515
De Man K, Van Laeken N, Schelfhout V, Fendler WP, Lambert B, Kersemans K et al (2022) 18F-PSMA-11 Versus 68Ga-PSMA-11 Positron Emission Tomography/Computed tomography for staging and biochemical recurrence of prostate Cancer: a prospective double-blind Randomised Cross-over Trial. Eur Urol 82(5):501–50935690515 10.1016/j.eururo.2022.05.010
Dietlein M Kobe C Kuhnert G Stockter S Fischer T Schomäcker K Comparison of [18F]DCFPyL and [68Ga]Ga-PSMA-HBED-CC for PSMA-PET imaging in patients with relapsed prostate Cancer Mol Imaging Biol 2015 17 4 575 584 10.1007/s11307-015-0866-0 26013479
Dietlein M, Kobe C, Kuhnert G, Stockter S, Fischer T, Schomäcker K et al (2015) Comparison of [(18)F]DCFPyL and [(68)Ga]Ga-PSMA-HBED-CC for PSMA-PET imaging in patients with relapsed prostate Cancer. Mol Imaging Biol 17(4):575–58426013479 10.1007/s11307-015-0866-0
Ergül N Yilmaz Güneş B Yücetaş U Toktaş MG Çermik TF 68Ga-PSMA-11 PET/CT in newly diagnosed prostate adenocarcinoma Clin Nucl Med 2018 43 12 e422 e427 10.1097/RLU.0000000000002289 30273204
Ergül N, Yilmaz Güneş B, Yücetaş U, Toktaş MG, Çermik TF (2018) 68Ga-PSMA-11 PET/CT in newly diagnosed prostate adenocarcinoma. Clin Nucl Med 43(12):e422–e42730273204 10.1097/RLU.0000000000002289
Farolfi A Calderoni L Mattana F Mei R Telo S Fanti S Current and emerging clinical applications of PSMA PET Diagnostic imaging for prostate Cancer J Nucl Med 2021 62 5 596 604 10.2967/jnumed.120.257238 33712536
Farolfi A, Calderoni L, Mattana F, Mei R, Telo S, Fanti S et al (2021) Current and emerging clinical applications of PSMA PET Diagnostic imaging for prostate Cancer. J Nucl Med 62(5):596–60433712536 10.2967/jnumed.120.257238
Hofman MS Lawrentschuk N Francis RJ Tang C Vela I Thomas P Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study Lancet 2020 395 10231 1208 1216 10.1016/S0140-6736(20)30314-7 32209449
Hofman MS, Lawrentschuk N, Francis RJ, Tang C, Vela I, Thomas P et al (2020) Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet 395(10231):1208–121632209449 10.1016/S0140-6736(20)30314-7
Kersemans K De Man K Courtyn J Van Royen T Piron S Moerman L Automated radiosynthesis of Al[18F]PSMA-11 for large scale routine use Appl Radiat Isot 2018 135 19 27 10.1016/j.apradiso.2018.01.006 29353193
Kersemans K, De Man K, Courtyn J, Van Royen T, Piron S, Moerman L et al (2018) Automated radiosynthesis of Al[18F]PSMA-11 for large scale routine use. Appl Radiat Isot 135:19–2729353193 10.1016/j.apradiso.2018.01.006
Koerber SA Utzinger MT Kratochwil C Kesch C Haefner MF Katayama S 68Ga-PSMA-11 PET/CT in newly diagnosed Carcinoma of the prostate: correlation of Intraprostatic PSMA Uptake with several clinical parameters J Nucl Med 2017 58 12 1943 1948 10.2967/jnumed.117.190314 28619734
Koerber SA, Utzinger MT, Kratochwil C, Kesch C, Haefner MF, Katayama S et al (2017) 68Ga-PSMA-11 PET/CT in newly diagnosed Carcinoma of the prostate: correlation of Intraprostatic PSMA Uptake with several clinical parameters. J Nucl Med 58(12):1943–194828619734 10.2967/jnumed.117.190314
Kuten J Fahoum I Savin Z Shamni O Gitstein G Hershkovitz D Head-to-Head comparison of 68Ga-PSMA-11 with 18F-PSMA-1007 PET/CT in staging prostate Cancer using histopathology and Immunohistochemical Analysis as a reference Standard J Nucl Med 2020 61 4 527 532 10.2967/jnumed.119.234187 31562225
Kuten J, Fahoum I, Savin Z, Shamni O, Gitstein G, Hershkovitz D et al (2020) Head-to-Head comparison of 68Ga-PSMA-11 with 18F-PSMA-1007 PET/CT in staging prostate Cancer using histopathology and Immunohistochemical Analysis as a reference Standard. J Nucl Med 61(4):527–53231562225 10.2967/jnumed.119.234187
Li R Cheng C Mao J Li D Cui B Li X Preparation of Al18F-PSMA-11 and its preliminary PET/CT imaging Chin J Nuclear Med Mol Imaging 2022 42 10 602 606
Li R, Cheng C, Mao J, Li D, Cui B, Li X et al (2022) Preparation of Al18F-PSMA-11 and its preliminary PET/CT imaging. Chin J Nuclear Med Mol Imaging 42(10):602–606
Lütje S Heskamp S Cornelissen AS Poeppel TD van den Broek SAMW Rosenbaum-Krumme S PSMA Ligands for Radionuclide Imaging and Therapy of prostate Cancer: clinical status Theranostics 2015 5 12 1388 1401 10.7150/thno.13348 26681984
Lütje S, Heskamp S, Cornelissen AS, Poeppel TD, van den Broek SAMW, Rosenbaum-Krumme S et al (2015) PSMA Ligands for Radionuclide Imaging and Therapy of prostate Cancer: clinical status. Theranostics 5(12):1388–140126681984 10.7150/thno.13348
Maurer T Gschwend JE Rauscher I Souvatzoglou M Haller B Weirich G Diagnostic efficacy of 68Gallium-PSMA Positron Emission Tomography compared to conventional imaging for Lymph Node Staging of 130 consecutive patients with intermediate to high risk prostate Cancer J Urol 2016 195 5 1436 1443 10.1016/j.juro.2015.12.025 26682756
Maurer T, Gschwend JE, Rauscher I, Souvatzoglou M, Haller B, Weirich G et al (2016) Diagnostic efficacy of (68)Gallium-PSMA Positron Emission Tomography compared to conventional imaging for Lymph Node Staging of 130 consecutive patients with intermediate to high risk prostate Cancer. J Urol 195(5):1436–144326682756 10.1016/j.juro.2015.12.025
Morris MJ Rowe SP Gorin MA Saperstein L Pouliot F Josephson D Diagnostic performance of 18F-DCFPyL-PET/CT in men with biochemically recurrent prostate Cancer: results from the CONDOR Phase III, Multicenter Study Clin Cancer Res 2021 27 13 3674 3682 10.1158/1078-0432.CCR-20-4573 33622706
Morris MJ, Rowe SP, Gorin MA, Saperstein L, Pouliot F, Josephson D et al (2021) Diagnostic performance of 18F-DCFPyL-PET/CT in men with biochemically recurrent prostate Cancer: results from the CONDOR Phase III, Multicenter Study. Clin Cancer Res 27(13):3674–368233622706 10.1158/1078-0432.CCR-20-4573
Mottet N van den Bergh RCN Briers E Van den Broeck T Cumberbatch MG De Santis M EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate Cancer-2020 update. Part 1: screening, diagnosis, and local treatment with curative intent Eur Urol 2021 79 2 243 262 10.1016/j.eururo.2020.09.042 33172724
Mottet N, van den Bergh RCN, Briers E, Van den Broeck T, Cumberbatch MG, De Santis M et al (2021) EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate Cancer-2020 update. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol 79(2):243–26233172724 10.1016/j.eururo.2020.09.042
Rahbar K Afshar-Oromieh A Bögemann M Wagner S Schäfers M Stegger L 18F-PSMA-1007 PET/CT at 60 and 120 minutes in patients with prostate cancer: biodistribution, tumour detection and activity kinetics Eur J Nucl Med Mol Imaging 2018 45 8 1329 1334 10.1007/s00259-018-3989-0 29541812
Rahbar K, Afshar-Oromieh A, Bögemann M, Wagner S, Schäfers M, Stegger L et al (2018) 18F-PSMA-1007 PET/CT at 60 and 120 minutes in patients with prostate cancer: biodistribution, tumour detection and activity kinetics. Eur J Nucl Med Mol Imaging 45(8):1329–133429541812 10.1007/s00259-018-3989-0
Rauscher I Krönke M König M Gafita A Maurer T Horn T Matched-pair comparison of 68Ga-PSMA-11 PET/CT and 18F-PSMA-1007 PET/CT: frequency of pitfalls and detection efficacy in biochemical recurrence after radical prostatectomy J Nucl Med 2020 61 1 51 57 10.2967/jnumed.119.229187 31253741
Rauscher I, Krönke M, König M, Gafita A, Maurer T, Horn T et al (2020) Matched-pair comparison of 68Ga-PSMA-11 PET/CT and 18F-PSMA-1007 PET/CT: frequency of pitfalls and detection efficacy in biochemical recurrence after radical prostatectomy. J Nucl Med 61(1):51–5731253741 10.2967/jnumed.119.229187
Rowe SP Buck A Bundschuh RA Lapa C Serfling SE Derlin T [18F]DCFPyL PET/CT for imaging of prostate Cancer Nuklearmedizin 2022 61 3 240 246 10.1055/a-1659-0010 35030637
Rowe SP, Buck A, Bundschuh RA, Lapa C, Serfling SE, Derlin T et al (2022) [18F]DCFPyL PET/CT for imaging of prostate Cancer. Nuklearmedizin 61(3):240–24635030637 10.1055/a-1659-0010
Sahlmann C-O Meller B Bouter C Ritter CO Ströbel P Lotz J Biphasic 68Ga-PSMA-HBED-CC-PET/CT in patients with recurrent and high-risk prostate carcinoma Eur J Nucl Med Mol Imaging 2016 43 5 898 905 10.1007/s00259-015-3251-y 26563122
Sahlmann C-O, Meller B, Bouter C, Ritter CO, Ströbel P, Lotz J et al (2016) Biphasic 68Ga-PSMA-HBED-CC-PET/CT in patients with recurrent and high-risk prostate carcinoma. Eur J Nucl Med Mol Imaging 43(5):898–90526563122 10.1007/s00259-015-3251-y
Siegel RL Miller KD Wagle NS Jemal A Cancer statistics, 2023 CA Cancer J Clin 2023 73 1 17 48 10.3322/caac.21763 36633525
Siegel RL, Miller KD, Wagle NS, Jemal A (2023) Cancer statistics, 2023. CA Cancer J Clin 73(1):17–4836633525 10.3322/caac.21763
Uprimny C Kroiss AS Decristoforo C Fritz J von Guggenberg E Kendler D 68Ga-PSMA-11 PET/CT in primary staging of prostate cancer: PSA and Gleason score predict the intensity of tracer accumulation in the primary tumour Eur J Nucl Med Mol Imaging 2017 44 6 941 949 10.1007/s00259-017-3631-6 28138747
Uprimny C, Kroiss AS, Decristoforo C, Fritz J, von Guggenberg E, Kendler D et al (2017) 68Ga-PSMA-11 PET/CT in primary staging of prostate cancer: PSA and Gleason score predict the intensity of tracer accumulation in the primary tumour. Eur J Nucl Med Mol Imaging 44(6):941–94928138747 10.1007/s00259-017-3631-6
van Leeuwen PJ Emmett L 18F-PSMA-11 as an attractive 68Ga-PSMA-11 alternative for prostate Cancer imaging Eur Urol 2022 82 5 510 511 10.1016/j.eururo.2022.06.001 35787936
van Leeuwen PJ, Emmett L (2022) 18F-PSMA-11 as an attractive 68Ga-PSMA-11 alternative for prostate Cancer imaging. Eur Urol 82(5):510–51135787936 10.1016/j.eururo.2022.06.001
Williams IS McVey A Perera S O’Brien JS Kostos L Chen K Modern paradigms for prostate cancer detection and management Med J Aust 2022 217 8 424 433 10.5694/mja2.51722 36183329
Williams IS, McVey A, Perera S, O’Brien JS, Kostos L, Chen K et al (2022) Modern paradigms for prostate cancer detection and management. Med J Aust 217(8):424–43336183329 10.5694/mja2.51722
Zhang Z Jia G Pan G Cao K Yang Q Meng H Comparison of the diagnostic efficacy of 68Ga-FAPI-04 PET/MR and 18F-FDG PET/CT in patients with pancreatic cancer Eur J Nucl Med Mol Imaging 2022 49 8 2877 2888 10.1007/s00259-022-05729-5 35243518
Zhang Z, Jia G, Pan G, Cao K, Yang Q, Meng H et al (2022) Comparison of the diagnostic efficacy of 68 Ga-FAPI-04 PET/MR and 18F-FDG PET/CT in patients with pancreatic cancer. Eur J Nucl Med Mol Imaging 49(8):2877–288835243518 10.1007/s00259-022-05729-5
Zhao G Ji B Head-To-Head comparison of 68Ga-PSMA-11 PET/CT and 99mTc-MDP bone scintigraphy for the detection of bone metastases in patients with prostate Cancer: a Meta-analysis AJR Am J Roentgenol 2022 219 3 386 395 10.2214/AJR.21.27323 35441529
Zhao G, Ji B (2022) Head-To-Head comparison of 68Ga-PSMA-11 PET/CT and 99mTc-MDP bone scintigraphy for the detection of bone metastases in patients with prostate Cancer: a Meta-analysis. AJR Am J Roentgenol 219(3):386–39535441529 10.2214/AJR.21.27323
