Biodistribution and radiation dosimetry of multiple tracers on total-body positron emission tomography/computed tomography

Introduction

Molecular imaging with positron emission tomography (PET) has greatly improved clinical management of human diseases, especially cancers (1). PET is a molecular imaging technique with unparalleled specificity and sensitivity. The specificity of PET imaging comes from the specific PET tracers prepared by radiochemical methods, and the use of these tracers is the key to demonstrate the power and versatility of PET imaging. PET tracers are bioactive compounds labeled with positron emission radionuclides that interact with specific proteins, enzymes, or biochemical processes in the body. PET imaging collects and visualizes information about these interactions to explore physiology, pharmacology, causes of disease, and therapeutic mechanisms in living systems. There are many tracers currently used in clinic setting, among which [¹⁸F]F-FDG, [⁶⁸Ga]Ga-PSMA-11, and [⁶⁸Ga]Ga-FAPI-04 are the most prominent tracers. [¹⁸F]F-FDG plays an important role in evaluating disease staging of various malignancies, detecting early disease recurrence, evaluating treatment response, predicting prognosis, and assessing the spread of inflammatory diseases (2). [⁶⁸Ga]Ga-PSMA-11 has high sensitivity for prostate cancer imaging. Several studies have shown that the detection rate of [⁶⁸Ga]Ga-PSMA-11 PET/CT is higher than that of conventional imaging methods (3,4). In parallel, [⁶⁸Ga]Ga-FAPI-04 PET/CT showed good pharmacokinetics in vivo and was applied in the characterization of different types of tumors (5,6). However, a head-to-head comparison of dynamic circulation, distribution, and uptake patterns as well as radiation doses for these three representative tracers is lacking. With traditional short-axis PET/CT scanners, it was unable to fulfill the tasks.

With the joint efforts of experts from multiple tertiary hospitals, we have published the first version of consensus reporting the advantageous applications of the uExplorer PET/CT (7). The uExplorer PET/CT has the advantages of an ultra-long axial field of view (FOV), ultra-high resolution and sensitivity, this heavy-duty large device allows us to see and know more than the fast PET/CT scans. Compared to conventional scanners, uExplorer has a 40× increase in total-body imaging sensitivity, a 6.3× increase in single organ signal-to-noise ratio (SNR), and significant improvements in target-to-background ratio (TBR) and contrast-to-noise ratio (CNR). Due to the comprehensive improvement of the software and hardware, quantitative analysis of total-body PET/CT is more accurate, and image quality is more optimized (8,9).

We aimed to use total-body uExplorer scanner in real-time dynamic mode, rather than traditional short-axis (15–30 cm axial FOV length) scanning, to achieve realistic and dynamic observations of the systemic biodistribution of multiple tracers and to calculate precise radiation doses. Besides its importance in radiation assessment, it also helps to optimize injection doses, compare differences in radionuclides, observe biodistribution characteristics of different drugs labeled with the same radionuclide, improve image quality, and simplify clinical workflow.

Methods

Radiopharmaceutical preparation

[¹⁸F]F-FDG, [⁶⁸Ga]Ga-PSMA-11 and [⁶⁸Ga]Ga-FAPI-04 were synthesized by Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University following the standard protocols (10-12).

Patient recruitment and characteristics

A total of 54 patients undergoing total-body PET/CT were retrospectively included in the study, including 30 patients with [¹⁸F]F-FDG, 10 patients with [⁶⁸Ga]Ga-PSMA-11, and 14 patients with [⁶⁸Ga]Ga-FAPI-04. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics board of Renji Hospital, School of Medicine, Shanghai Jiao Tong University and informed consent was taken from all the patients.

Total-body PET/CT scanning protocol

All 54 patients underwent dynamic scanning of whole body for 60 minutes using a total-body PET/CT scanner (uExplorer, United Imaging Healthcare) (13). History and physical examination were performed prior to PET/CT examination and all patients were asked to urinate before examination to ensure relative comfort during examination. For individual scanning, the patient was comfortably supine on the examination mattress during dynamic acquisition to achieve optimal imaging position and avoid motion artifacts. The CT scan tube voltage was 120 kV, and the dose was adjusted by automatic mas technology (14). Simultaneous PET acquisition was performed when the tracer was injected at the bedside, and maximum PET FOV was 194 cm. The PET raw data was reconstructed into 92 frames (24×5 s, 20×30 s, 48×60 s), and reconstruction parameters included standard ordered subset expectation maximization (OSEM)algorithm, time-of-flight (TOF), point-spread function (PSF) algorithms, 3 iterations, 20 subsets, 256×256 matrix, 600 mm FOV, 2.886 mm slice thickness, Gaussian post-filter with 3 mm full width at half maximum (FWHM). In addition, PET reconstruction incorporated standard corrections such as attenuation, scattering, randomization, dead time, and normalization.

Whole-body time-activity curves

Senior and experienced nuclear medicine physicians (W Wei and J Liu) used Pmod4.0 software (PMOD 4.0 Fusion, PMOD Technologies LLC, Zurich, Switzerland) (15) to quantitatively analyze the dynamic sequence of 92 frames. Taking into account the partial volume effect, the delineated volume of interest (VOI) was slightly smaller than the actual size of the organ. Tracer kinetics and cumulative organ activity were calculated using VOI to generate time-activity curves to visualize changes in subject’s organ uptake and calculate internal radiation dose (16). Data and time-activity curves of heart were derived from the left ventricle.

Radiation effective dose estimates

Organ time-activity curves (TACs) were analyzed by PET using PMOD (Kinetic Modeling Module). The software calculated the trapezoidal integral over 60 minutes to obtain the organ cumulative activity (Bq-hr/Bq). The isotope tail was checked by pmod using the radioactive decay shape for the integration from the end of the last frame to infinity. Effective doses and individual organ doses were calculated for each patient using standard organ volumes with the OLINDA/EXM (version OLINDA/EXM 1.0, Vanderbilt University, Nashville, TN, USA) (17). The bladder wall had dynamic characteristics, and the interval between bladder urination was assumed to be two hours.

Results

Patient characteristics

The patient data are shown in Table 1. History and physical examination were performed prior to PET/CT examination, and all patients were asked to urinate before examination to ensure relative comfort during examination.

Biodistribution and radiation dose calculation

Representative whole-body PET/CT images of the three tracers at different time points are shown in Figures 1-3. Figures 1-3 show the maximum intensity projection (MIP) images of [¹⁸F]F-FDG, [⁶⁸Ga]Ga-PSMA-11, and [⁶⁸Ga]Ga-FAPI-04, respectively.

Figure 1 Whole body maximum intensity projection of [¹⁸F]F-FDG. 40–45 s, pulmonary circulation distribution; 55–60 s, circulation distribution throughout the body; 150–180 s, tumor and multiple bone fracture uptake; 450–480 s, urinary bladder excretion; 3,360–3,420 s, tumor and multiple bone fracture concentration.

Figure 2 Whole body maximum intensity projection of [⁶⁸Ga]Ga-PSMA-11. 20–25 s, distribution of pulmonary circulation; 40–45 s, circulation distribution throughout the body; 180–210 s, imaging of parotid and submandibular glands; 630–660 s, imaging of urinary bladder; 1,680–1,740 s, decreased pulmonary circulation.

Figure 3 Whole body maximum intensity projection of [⁶⁸Ga]Ga-FAPI-04. 30–35 s, distribution of pulmonary circulation; 70–75 s, circulation distribution throughout the body; 240–270 s, urinary bladder imaging; 420–450 s, tumor concentration; 3,300–3,360 s, decreased renal uptake.

Consistent [¹⁸F]F-FDG biodistribution was observed in all major organs of 30 patients, and TAC analysis results are shown in Figure 4 and Table 2. The peak activity concentrations from high to low were urinary bladder, heart, kidney, spleen, liver, brain, stomach, lung, muscle, bone. Tracer uptake in muscle, stomach and bone showed a trend of rapid increase and steady uptake (Figure 4A). Among them, the activity concentration of muscle was the highest (3.10E+06±7.30E+05 kBq/cc), and the time to plateau in stomach was the shortest (7.92E+02±1.18E+03 s). Rapid increase of the tracer followed by rapid decrease in heart, kidney, liver, lung, and spleen was observed (Figure 4B). Peak times were similar for heart and lung (7.35E+01±6.65E+01 and 9.43E+01±1.17E+02 s), while stomach had the shortest peak time (7.92E+02±1.18E+03 s). The maximum activity concentration of liver and spleen were 2.69E+07±6.93E+06 kBq/cc and 2.85E+07±1.14E+07 kBq/cc, respectively. Brain and urinary bladder had similar TAC patterns, which were gradually increasing (Figure 4C,4D). Urinary bladder initially had no tracer uptake due to limited renal clearance at early time points. During 60 minutes of dynamic collection, tracer uptake in the brain and bladder continued to increase.

Figure 4 TAC curves of [¹⁸F]F-FDG in major organs, including muscle, stomach and bone (A), heart, kidney, liver, lung and spleen (B), brain (C), urinary bladder (D). TAC, time-activity curve.

The results of TAC analysis of [⁶⁸Ga]Ga-PSMA-11 biodistribution in major organs of 10 patients are shown in Figure 5 and Table 3. The peak activity concentrations from high to low were urinary bladder, kidney, heart, submandibular gland, spleen, parotid gland, liver, stomach, lung, muscle, brain, bone. Tracer uptake in liver, spleen, muscle and bone showed a trend of rapid increase and slow decrease (Figure 5A,5B). Among them, spleen had the highest peak activity concentration (1.73E+07±5.14E+06 kBq/cc), and bone had the shortest peak time (4.32E+02±1.77E+02 s). Rapid uptake of tracer followed by a rapid decrease occurred in the heart, stomach, brain and lung (Figure 5C,5D). Peak times of heart and lung were similar (6.15E+01±2.32E+01 and 6.20E+01±2.35E+01 s), while brain had the lowest peak activity concentration (9.73E+05±3.72E+05 kBq/cc). Tracer uptake in the kidney and urinary bladder was gradually increased (Figure 5E), with no uptake in the early stage of urinary bladder, a trend of fast uptake in the early stage of the kidney, and a fast uptake rate in the late stage of urinary bladder. Uptake patterns in the parotid and submandibular glands increased gradually over time (Figure 5F), and its peak time was close to urinary bladder. The peak of parotid gland was close to spleen. From the dynamic uptake patterns of parotid and submandibular glands shown in Figure 5F, it appears that vitamin C administration at an early time point or controlled release of vitamin C over the acquisition time may better decrease the accumulation of [⁶⁸Ga]Ga-PSMA-11 in the parotid and submandibular glands. The hypothesis needs to be validated in future studies.

Figure 5 TAC curves of [⁶⁸Ga]Ga-PSMA-11 in the major organs, including liver and spleen (A), muscle and bone (B), heart and stomach (C), brain and lung (D), kidney and urinary bladder (E), parotid gland and submandibular gland (F). TAC, time-activity curve.

The results of TAC analysis of [⁶⁸Ga]Ga-FAPI-04 biodistribution in major organs of 14 patients are shown in Figure 6 and Table 4. The peak activity concentrations from high to low were urinary bladder, heart, kidney, spleen, liver, stomach, lung, muscle, brain, bone. Tracer uptake in brain, lung, liver, spleen, bone, heart, kidney, and stomach showed a trend of rapid increase and rapid decrease (Figure 6A-6C). Heart had the highest peak activity concentration (3.15E+07±1.43E+07 kBq/cc). Peak times of heart and lung are similar (5.46E+01±2.52E+01 and 5.54E+01±2.66E+01 s). Brain and bone had lower peak activity concentrations (1.39E+06±6.22E+05 and 1.36E+06±5.46E+05 kBq/cc). In muscle, there was a rapid uptake of the tracer followed by a slow decrease (Figure 6D). The uptake trend of urinary bladder was consistent with that of [¹⁸F]F-FDG, with no uptake in the initial stage and a gradual increase at the later stage (Figure 6E).

Figure 6 TAC curves of [⁶⁸Ga]Ga-FAPI-04 in the major organs, including brain and lung (A), liver, spleen and bone (B), heart, kidney and stomach (C), muscle (D), urinary bladder (E). TAC, time-activity curve.

Effective doses of various tracers in organs of interest were calculated using the OLINDA/EXM software. Table 5 shows the standardized cumulated activity values of multiple tracer organs. It can be seen from Table 6 that effective radiation dose of [⁶⁸Ga]Ga-PSMA-11 is the lowest (1.47E−02±2.27E−03 mSv/MBq), and the mean effective dose is slightly higher than that of ¹⁸F-PSMA-11 (1.28E−02 mSv/MBq) reported by Piron et al. (18). The effective doses of [¹⁸F]F-FDG and [⁶⁸Ga]Ga-FAPI-04 were similar (2.52E−02±1.04E−02 and 2.23E−02±7.29E−03 mSv/MBq). The difference in the mean effective dose is that the radiation dose of [¹⁸F]F-FDG is lower than that reported by Deloar et al. (2.9E−02 mSv/MBq) (19), and the effective dose of [⁶⁸Ga]Ga-FAPI-04 is higher than that reported by Giesel et al. (1.64E−02 mSv/MBq) (5). The injection dose of [¹⁸F]F-FDG (285.1±43.74 MBq) was the highest, partially resulted in the highest internal radiation dose in a single examination.

Discussion

Total-body PET/CT has a long field of view and a wider detection angle, which is 40 times more sensitive than the traditional short-axis PET/CT. High-sensitivity and rapid scanning provide the opportunity to suppress motility of the gastrointestinal tract, making the fusion of PET and CT more accurate (20,21). Total-body uninterrupted continuous dynamic scanning is beneficial for simultaneous analysis of total-body pharmacokinetics of radiotracers and radioligands. Moreover, the calculated radiation dose is more accurate.

Based on 1-hour uninterrupted TAC analysis, [⁶⁸Ga]Ga-PSMA-11 and [⁶⁸Ga]Ga-FAPI-04 showed the same uptake trends in brain, lung, heart, stomach, and bone, but different uptake trends in other organs. The internal radiation doses of the same radionuclide-labeled PSMA (1.47E−02±2.27E−03 mSv/MBq) and FAPI (2.23E−02±7.29E−03mSv/MBq) are quite different, and the difference may be internal (such as the properties of the precursors and the associated pharmacokinetics) or externally (such as differences in injection doses of the radiopharmaceuticals) (22). The injection dose of [¹⁸F]F-FDG was the highest (285.1±43.74 MBq), and the total internal radiation dose in a single examination was higher than that of [⁶⁸Ga]Ga-PSMA-11 and [⁶⁸Ga]Ga-FAPI-04. [⁶⁸Ga]Ga-PSMA-11 had the lowest radiation dose (1.47E−02±2.27E−03 mSv/MBq), and the mean effective dose was slightly higher than that of Piron et al. (1.28E−02 mSv/MBq) (18). The possible reason was that different nuclide markers resulted in different cumulative activity of organs. The article reported that oral administration of vitamin C decreased [⁶⁸Ga]Ga-PSMA-11 accumulation in salivary glands during examination (23). In the study by Yu et al., vitamin C was given 30 min after starting the dynamic PET acquisition (23). Radiation doses of [¹⁸F]F-FDG and [⁶⁸Ga]Ga-FAPI-04 were comparable (2.52E−02±1.04E−02 mSv/MBq and 2.23E−02±7.29E−03 mSv/MBq), the effective dose of [¹⁸F]F-FDG was close to that reported in the literature (24). The corresponding dose of [⁶⁸Ga]Ga-FAPI-04 was higher than that reported by Giesel et al. (1.64E−02 mSv/MBq) (5). In the literature, fitting functions were used for integration from the last measured point in time to infinity instead of using the radioactive decay shape for the integration. The mean effective dose of [¹⁸F]F-FDG was lower than that reported by Deloar et al. (2.9E−02 mSv/MBq) (19), total-body dynamic acquisition provided more realistic biological distribution data, and the calculated shorter retention time resulted in a lower calculated effective dose. Compared to Fluorine-18 (¹⁸F), gallium-68 (⁶⁸Ga) has a relatively high positron energy, resulting in a large number of image quality degradations. In addition, the presence of statistical noise further degrades image quality. The difference of reconstruction methods will also affect the image quality (25). From the subjective point of view of image quality, the image noise of ¹⁸F-labeled FDG is lower than that of ⁶⁸Ga-labeled PSMA and FAPI (26).

Previous studies of these three tracers lacked a macroscopic and systematic interpretation of the biodistribution of whole-body organs, and the main limitation was that multi-bed PET/CT scans could not truly study whole body biodistribution and radiation dose of the tracers (19,24,27); the missing of multiple time points for some organs leading to biases in subsequent dose estimates. Short-axis PET/CT can design different single-bed scan time according to the peak time of the three tracers. This enables faster scanning of multiple organs throughout the body and avoids the loss of peak data for some organs. At present, there is no literature reporting radiation dose of [⁶⁸Ga]Ga-FAPI-04 and [⁶⁸Ga]Ga-PSMA-11 calculated by total-body PET/CT scanning. A more accurate description of the biodistribution profiles of [⁶⁸Ga]Ga-FAPI-04 and [⁶⁸Ga]Ga-PSMA-11 and the calculation of radiation dose will better guide radionuclide therapy. For instance, accurate dose assessment of [⁶⁸Ga]Ga-PSMA could be of great value in further optimizing the clinical application of long half-life ¹⁷⁷Lu-labeled PSMA inhibitors (e.g., [¹⁷⁷Lu]Lu-PSMA-617) (28).

One of the limitations of our study is the limited number of [⁶⁸Ga]Ga-PSMA-11 and [⁶⁸Ga]Ga-FAPI-04 dynamic scans, with only 10 and 14 cases, respectively. More cases and volunteers will be recruited for in-depth and comprehensive research in the future. Another limitation is the lack of time points after 60 minutes, mainly due to the movement of the patient during long-term dynamic acquisitions, which affects the accuracy of the results, and more time points can be added to calculate more precise radiation dose estimation. In addition, the truncation artifact generated by the patient’s hands on the sides of the body during dynamic scanning may interfere with the attenuation correction of PET images (29).

The effective dose of the radioactive tracer for a single PET imaging session was lower than 50 mSv per year established by the National Institutes of Health for this study (30), allowing for multiple PET scans per year of the same subject. In the future, we plan to achieve longer PET dynamic PET scan cycles in eligible healthy volunteers, combined with more time points to study whole-body biological distribution and radiation dose, and will consider larger sample sizes and subjects with different characteristics. In addition, biological distribution and dosimetry calculation of therapeutic radiopharmaceuticals remains to be explored in the future studies. Finally, we also analyzed indications and diagnostic performance of total-body dynamic PET/CT scanning using the above three radioactive tracers, simplifying the clinical workflows and improving the diagnostic performances.

Conclusions

Through total-body uninterrupted dynamic PET/CT scanning, we observed that [¹⁸F]F-FDG, [⁶⁸Ga]Ga-PSMA-11 and [⁶⁸Ga]Ga-FAPI-04 had good biodistribution in human organs and accurately calculated the corresponding effective doses. It will be helpful to optimize injection dose and simplify clinical workflow in the future studies. Short-axis PET/CT can optimize the dynamic acquisition scheme and static imaging time based on the biological distribution and peak time of multiple organs with different tracers, achieving more accurate pharmacokinetic analysis and clinical diagnosis.

Acknowledgments

The authors want to thank all the clinical and research staff at the Department of Nuclear Medicine, Renji Hospital, Shanghai Jiao Tong University for their technical assistance and helpful discussions.

Funding: This work was supported in part by the National Key Research and Development Program of China (Nos. 2020YFA0909000 and 2021YFA0910000), the National Natural Science Foundation of China (Nos. 82001878 and 82171972), and the Shanghai Rising-Star Program (No. 20QA1406100).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-1418/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics board of Renji Hospital, School of Medicine, Shanghai Jiao Tong University and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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