A first-in-man study of [18F] FEDAC: a novel PET tracer for the 18-kDa translocator protein.

PURPOSE: N-benzyl-N-methyl-2-[7, 8-dihydro-7-(2-[18F] fluoroethyl) -8-oxo-2-phenyl-9H-purin-9-yl] acetamide ([18F] FEDAC) is a novel positron emission tomography (PET) tracer that targets the translocator protein (TSPO; 18 kDa) in the mitochondrial outer membrane, which is known to be upregulated in various diseases such as malignant tumors, neurodegenerative diseases, and neuroinflammation. This study presents the first attempt to use [18F]FEDAC PET/CT and evaluate its biodistribution as well as the systemic radiation exposure to the radiotracer in humans. MATERIALS AND METHODS: Seventeen whole-body [18F]FEDAC PET/CT (injected dose, 209.1 ± 6.2 MBq) scans with a dynamic scan of the upper abdomen were performed in seven participants. Volumes of interest were assigned to each organ, and a time-activity curve was created to evaluate the biodistribution of the radiotracer. The effective dose was calculated using IDAC-Dose 2.1. RESULTS: Immediately after the intravenous injection, the radiotracer accumulated significantly in the liver and was subsequently excreted into the gastrointestinal tract through the biliary tract. It also showed high levels of accumulation in the kidneys, but showed minimal migration to the urinary bladder. Thus, the liver was the principal organ that eliminated [18F] FEDAC. Accumulation in the normal brain tissue was minimal. The effective dose estimated from biodistribution in humans was 19.47 ± 1.08 µSv/MBq, and was 3.60 mSV for 185 MBq dose. CONCLUSION: [18F]FEDAC PET/CT provided adequate image quality at an acceptable effective dose with no adverse effects. Therefore, [18F]FEDAC may be useful in human TSPO-PET imaging.

Investigating neural dysfunction with abnormal protein deposition in Alzheimer's disease through magnetic resonance spectroscopic imaging, plasma biomarkers, and positron emission tomography.

In Alzheimer's disease (AD), aggregated abnormal proteins induce neuronal dysfunction. Despite the evidence supporting the association between tau proteins and brain atrophy, further studies are needed to explore their link to neuronal dysfunction in the human brain. To clarify the relationship between neuronal dysfunction and abnormal proteins in AD-affected brains, we conducted magnetic resonance spectroscopic imaging (MRSI) and assessed the neurofilament light chain plasma levels (NfL). We evaluated tau and amyloid-ß depositions using standardized uptake value ratios (SUVRs) of florzolotau (18F) for tau and 11C-PiB for amyloid-ß positron emission tomography in the same patients. Heatmaps were generated to visualize Z scores of glutamate to creatine (Glu/Cr) and N-acetylaspartate to creatine (NAA/Cr) ratios using data from healthy controls. In AD brains, Z score maps revealed reduced Glu/Cr and NAA/Cr ratios in the gray matter, particularly in the right dorsolateral prefrontal cortex (rDLPFC) and posterior cingulate cortex (PCC). Glu/Cr ratios were negatively correlated with florzolotau (18F) SUVRs in the PCC, and plasma NfL levels were elevated and negatively correlated with Glu/Cr (P = 0.040, r = -0.50) and NAA/Cr ratios (P = 0.003, r = -0.68) in the rDLPFC. This suggests that the abnormal tau proteins in AD-affected brains play a role in diminishing glutamate levels. Furthermore, neuronal dysfunction markers including Glu/tCr and NAA/tCr could potentially indicate favorable clinical outcomes. Using MRSI provided spatial information about neural dysfunction in AD, enabling the identification of vulnerabilities in the rDLPFC and PCC within the AD's pathological context.

[The Questionnaire Survey of Japanese Practice and Environment for Targeted Radionuclide Therapy in 2021].

PURPOSE: Recently, the targeted radionuclide therapy (TRT) was urgently required to adapt the practice and environment because of the implementation of novel therapeutic radiopharmaceuticals such as alpha- and beta- radionuclides therapy. The present study aimed to clarify the questionnaire survey with the current situation (safety controls for workers and patients) at Japanese TRT facilities. METHODS: The massive questionnaire survey, 2 months from October to November 2021, was conducted among nationwide 251 facilities that have performed TRT in the past two years. The alpha- and beta- therapeutic radiopharmaceuticals were categorized and answered by one representative of the facility under anonymity. We analyzed the actual situation of each facility related to occupational exposure, radiation protection, contamination inspection, patient release criteria, and dosimetry for TRT. RESULTS: The survey response rate was 69.1% (174 facilities). About 75% of these facilities reported that they either follow the guidelines or take their own measures to reduce occupational exposure. The confirmed means of patient release criteria were 68.0% with the administered radioactivity and 87.2% with the ambient dose rate. The cold run was not performed for the first time at 15.0% and 10.0% of the facilities for ß- and α-emitting radionuclides, respectively. The facilities without attachment syringe shields were 39.2% for alpha-radionuclides therapy and 20.3% for beta-radionuclides therapy. CONCLUSION: We clarified the Japanese problem for TRT practice and environment by the questionnaire survey. Our findings indicated that the Japanese guidelines and manuals for TRT were not partly followed in the nationwide facilities.

Intraocular Water Movement Visualization Using 1 H-MRI With Eye Drops of O-17-Labeled Saline: First-in-Human Study.

BACKGROUND: Visualization of aqueous humor flow in MR contrast images using gadolinium is challenging because of the delayed contrast effects associated with the blood-retinal and blood-aqueous humor barriers. However, oxygen-17 water (H2 17 O) might be used as an ocular contrast agent. PURPOSE: To observe the distribution of H2 17 O in the human eye, and its flow in and out of the anterior chamber, using dynamic T2-weighted MRI. STUDY TYPE: Prospective. POPULATION: Six ophthalmologically normal volunteers (20-37 years, six females). FIELD STRENGTH/SEQUENCE: A 3 T/dynamic T2-weighted MRI. ASSESSMENT: H2 17 O eye drops were administered to the right eye. Time-series images were created by subtracting the image before the eye drops from each of the images obtained after the eye drops. The normalized signal intensity of the right anterior chamber (nAC) was obtained by dividing the signal intensity of the right anterior chamber region by that of the left. The inflow and outflow constants of H2 17 O and H2 17 O concentration were calculated from the nAC. STATISTICAL TESTS: A paired t-test was used to compare the flow-related values and temporal changes in signal intensity. P-values < 0.05 were considered statistically significant. RESULTS: Significantly decreased signal intensity was observed in the right anterior chamber but not the right vitreous body (P = 0.39). The nAC signal intensity decreased significantly and then recovered. The inflow and outflow constants were 0.36-0.94 min-1 and 0.023-0.13 min-1 , respectively. The maximum H2 17 O concentration was 0.078%-0.24%. DATA CONCLUSION: H2 17 O were distributed in the anterior chamber. The H2 17 O inflow into the anterior chamber was significantly faster than that of the outflow. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

[S-methyl-11C]-L-methionine positron emission tomography/computed tomography imaging parameters to evaluate early response for esophageal cancer with neoadjuvant carbon ion radiotherapy.

This study aimed to evaluate the uptake of the clinical effectiveness of [S-methyl-11C]-L-methionine positron emission tomography/computed tomography (MET PET/CT) in patients with esophageal cancer and to investigate MET PET/CT imaging parameters to assess early response for esophageal cancer with neoadjuvant carbon ion radiotherapy (CIRT). MET PET/CT scans were performed in nineteen patients before and 3 weeks after completion of CIRT. After Surgery, the effect of neoadjuvant CIRT was investigated by examining the relationship between each parameter of MET uptake and the histological assessment (grade and tumor residual ratio). Four parameters of MET uptake were the maximum and minimum standardized uptake values of pre and post CIRT (pre-SUVmax, pre-SUVmean, post-SUVmax, and post-SUVmean). MET PET/CT imaging of esophageal cancer was clearly demonstrated. The post-SUVmax was the most suitable parameter. When the cutoff value was set as post-SUVmax = 6.21, the sensitivity, the specificity, and the accuracy of Grades 3 were 100.0%, 63.6%, and 78.9%, respectively. And there was a positive relationship between the tumor residual ratio and post-SUVmax (R2 = 0.38, p < 0.005). MET PET/CT is clinically useful for the assessment of early response to neoadjuvant CIRT in esophageal cancer. Particularly, post-SUVmax is considered a promising PET imaging parameter.

Clinical value of PET/CT with carbon-11 4DST in the evaluation of malignant and benign lung tumors.

OBJECTIVES: The aim of this study was to assess the clinical value of [11C]4DST uptake in patients with lung nodules, including benign and malignant tumors, and to assess the correlation between [11C]4DST uptake and proliferative activity of tumors in comparison with [18F]FDG uptake. METHODS: Twenty-six patients (22 males and 4 females, mean age of 65.5-year-old) were analyzed in this prospective study. Patients underwent [11C]4DST and [18F]FDG PET/CT imaging on the same day. Diagnosis of each lung nodule was confirmed by histopathological examination of tissue specimens at surgery, or during clinical follow-up after the PET/CT studies. To assess the utility of the semi-quantitative evaluation method, the SUVmax was calculated of [11C]4DST and [18F]FDG uptake by the lesion. Proliferative activities of each tumor as indicated by the immunohistochemical Ki-67 index was also estimated using surgical specimens of patients. Then the relationship between the SUVmax of both PET/CT and the Ki-67 index was examined. Furthermore, the relationship between the uptake of [11C]4DST or [18F]FDG and the histopathological findings, the clinical stage, and the clinical outcome of patients were also assessed. RESULTS: There was a positive linear relationship between the SUVmax of [11C]4DST images and the Ki-67 index (Correlation coefficients = 0.68). The SUVmax of [11C]4DST in the 26 lung nodules were 1.65 ± 0.40 for benign lesions, 3.09 ± 0.83 for adenocarcinomas (P < 0.001 between benign and adenocarcinoma), and 2.92 ± 0.58 for SqCCs (P < 0.001 between benign and SqCC). Whereas, the SUVmax of [18F]FDG were 2.38 ± 2.27 for benign lesions, 6.63 ± 4.24 for adenocarcinomas (n.s.), and 7.52 ± 2.84 for SqCCs (n.s.). The relationship between TNM tumor stage and the SUVmax of [11C]4DST were 2.54 ± 0.37 for T1, 3.48 ± 0.57 for T2, and 4.17 ± 0.72 for T3 (P < 0.005 between T1 and T2, and P < 0.001 between T1 and T3). In comparison with the TNM pathological stage, SUVmax of [11C]4DST were 2.63 ± 0.49 for stage I, 3.36 ± 0.23 for stage II, 3.40 ± 1.12 for stage III, and 4.65 for stage IV (P < 0.05 between stages I and II). In comparison of the clinical outcome, the SUVmax of [11C]4DST were 2.72 ± 0.56 for the no recurrence (No Rec.) group, 3.10 ± 0.33 for the recurrence-free with adjuvant chemotherapy after the surgery (the No Rec. Adjv. CTx. group) and 4.66 ± 0.02 for the recurrence group (Rec. group) (P < 0.001 between the No Rec and Rec. groups, and P < 0.005 between the No Rec. Adjv. CTx. and Rec. groups). CONCLUSIONS: PET/CT with [11C]4DST is as feasible for imaging of lung tumors as [18F]FDG PET/CT. For diagnosing lung tumors, [11C]4DST PET is useful in distinguishing benign nodules from malignancies. [11C]4DST uptake in lung carcinomas is correlated with the proliferative activity of tumors, indicating a promising noninvasive PET imaging of DNA synthesis in malignant lung tumors.

[Radiological Technology for Targeted Radionuclide Therapy].

Targeted radioisotope therapy (TRT) is a radiotherapy using radioisotope or drug incorporating it and has been used as a treatment for selectively irradiating cancer cells. In recent years, interest in TRT has increased due to improvements in radionuclide production technology, development of new drugs and imaging modalities, and improvements in radiation technology. In order to enhance the effect of TRT, measurement of individual radiation doses to tumor tissue and organs at risk is important using highly quantitative nuclear medicine images. In this paper, we present a review of literature on optimization of TRT, which is a new research area from the perspective of radiation technology.

Assessment of SPECT-CT fusion images and semi-quantitative evaluation using SUV in 123I-IMP SPECT in patients with choroidal melanoma.

OBJECTIVES: The aim of this study was to assess the diagnostic ability of N-isopropyl-p-[I-123] iodoamphetamine (IMP) SPECT semi-quantitative evaluation based on the standardized uptake value (SUV) in patients with choroidal melanoma. The secondary aim was to investigate the 6-h IMP SPECT imaging in comparison with 24-h imaging. METHODS: Twenty-five patients (14 males and 11 females, mean age of 59.2-year-old) were analyzed in this retrospective study. Patients underwent 24-h IMP SPECT imaging with a gamma camera after intravenous injection of IMP. Twelve of 25 patients underwent 6-h SPECT imaging in addition to the 24-h imaging. All acquired SPECT images were fused with CT images using an image-analysis software. To assess the utility of semi-quantitative evaluation method, we introduced an image evaluation method using SUVmax comparing with conventional count-based uptake index (UI) evaluation of the lesion. Volumes-of-interest (VOIs) for SUVmax and regions-of-interest (ROIs) for UI were drawn referring to the SPECT-CT fusion image. Then the relationship between the 6- and 24-h images was examined both in SUV and UI evaluation. Furthermore, the relationship between the size category classification (SCC) by UICC/AJCC: 1-4 scales and each semi-quantitative value using SUVmax and UI was also assessed. RESULTS: SUVmax of the tumor was significantly higher than that of the normal side; 2.37 ± 0.88 and 1.77 ± 0.39 (P < 0.05) on 6-h image, 4.17 ± 1.73 and 2.04 ± 0.45 (P < 0.001) on 24-h image, respectively. UI of the tumor was also significantly higher than that of the normal side; 2.24 ± 0.67 and 1.53 ± 0.35 (P < 0.01) on 6-h image, 3.79 ± 1.24 and 1.67 ± 0.44 (P < 0.001) on 24-h image, respectively. There was a strong significant linear relationship in the evaluation with SUVmax between 6- and 24-h on the tumor side (R2 = 0.88, P < 0.0001), compared to that with Tumor-UI (R2 = 0.35, P < 0.05). In addition, SUVmax of the tumor clearly differentiated the SCC of the tumor category 4 from that of category 1, where SUVmax of the tumor for categories 1‒4 were 2.56 ± 0.59, 4.33 ± 1.92, 4.63 ± 1.45, and 5.73 ± 1.69, respectively (P < 0.05, for categories 1 and 4). CONCLUSIONS: The semi-quantitative evaluation by SUV of 123I-IMP SPECT images fused with CT images is useful for detecting choroidal melanoma. Moreover, 6-h imaging with SUV-based evaluation of 123I-IMP SPECT is promising compared to the conventional count-based UI evaluation method. Trial registration This study is registered in UMIN Clinical Trials Registry (UMIN-CTR) as UMIN study ID: UMIN000038174.

Performance evaluation of a whole-body prototype PET scanner with four-layer DOI detectors.

Parallax error caused by the detector crystal thickness degrades spatial resolution at the peripheral regions of the field-of-view (FOV) of a scanner. To resolve this issue, depth-of-interaction (DOI) measurement is a promising solution to improve the spatial resolution and its uniformity over the entire FOV. Even though DOI detectors have been used in dedicated systems with a small ring diameter such as for the human brain, breast and small animals, the use of DOI detectors for a large bore whole-body PET system has not been demonstrated yet. We have developed a four-layered DOI detector, and its potential for a brain dedicated system has been proven in our previous development. In the present work, we investigated the use of the four-layer DOI detector for a large bore PET system by developing the world's first whole-body prototype. We evaluated its performance characteristics in accordance with the NEMA NU 2 standard. Furthermore, the impact of incorporating DOI information was evaluated with the NEMA NU 4 image quality phantom. Point source images were reconstructed with a filtered back projection (FBP), and an average spatial resolution of 5.2 ± 0.7 mm was obtained. For the FBP image, the four-layer DOI information improved the radial spatial resolution by 48% at the 20 cm offset position. The peak noise-equivalent count rate (NECR) was 22.9 kcps at 7.4 kBq ml-1 and the scatter fraction was 44%. The system sensitivity was 5.9 kcps MBq-1. For the NEMA NU 2 image quality phantom, the 10 mm sphere was clearly visualized without any artifacts. For the NEMA NU 4 image quality phantom, we measured the phantom at 0, 10 and 20 cm offset positions. As a result, we found the image with four-layer DOI could visualize the 2 mm-diameter hot cylinder although it could not be recognized on the image without DOI. The average improvements in the recovery coefficients for the five hot rods (1-5 mm) were 0.3%, 4.4% and 26.3% at the 0, 10 and 20 cm offset positions, respectively (except for the 1 mm-diameter rod at the 20 cm offset position). Although several practical issues (such as adding end-shields) remain to be addressed before the scanner is ready for clinical use, we showed that the four-layer DOI technology provided higher and more uniform spatial resolution over the FOV and improved contrast for small uptake regions located at the peripheral FOV, which could improve detectability of small and distal lesions such as nodal metastases, especially in obese patients.

First prototyping of a dedicated PET system with the hemisphere detector arrangement.

A strong demand is expected for high-sensitivity, high-resolution and low-cost brain positron emission tomography (PET) imaging for early diagnosis of dementia, as well as for general neuroscience studies. Therefore, we have proposed novel geometries of a hemisphere detector arrangement for high-sensitivity brain imaging, in which an add-on detector at the chin position or neck position helps in sensitivity uniformity improvement. In this study, we developed the first prototype system for proof-of-concept using four-layer depth-of-interaction detectors, each of which consisted of 16 × 16 × 4 Zr-doped GSO crystals with dimensions of 2.8 × 2.8 × 7.5 mm3 and a high-sensitivity 64-channel flat-panel photomultiplier tube. We used 47 detectors to form a hemisphere detector with a hemisphere shape of 25 cm inner diameter and 50 cm outer diameter, and we used seven detectors for each of the add-on detectors. The total detector number of 54 was about one-fourth that of a typical whole-body PET scanner. The hemisphere detector for the prototype system was realized by multiple rings having different numbers of detectors and a cross-shaped top detector unit covering the top. Performance evaluation showed uniform spatial resolutions of 3-4 mm by the filtered back-projection method. Imaging tests of a hot-rod phantom done with an iterative method were able to resolve 2.2 mm rods. Peak sensitivity was measured as more than 10% at a region near the top of the head, which was achieved with the help of the top detector unit. In addition, using the prototype system, we performed the first FDG clinical test with a healthy volunteer. The results showed that the proposed geometries had high potential for realizing high-sensitivity, high-resolution, and low-cost brain PET imaging. As for the add-on detector position, it was shown that the neck position resulted in higher sensitivity and wider field of view (FOV) than the chin position because the add-on detector at the neck position can be placed continuously to the hemisphere detector and close to the FOV.

Modified NEMA NU-2 performance evaluation methods for a brain-dedicated PET system with a hemispherical detector arrangement.

Brain PET imaging has important roles in neurology, neuro-oncology and molecular imaging research. We have developed a helmet-type PET prototype and have shown that the proposed hemispherical geometry had high potential for realizing high-sensitivity and low-cost brain imaging. However, there is no standard performance evaluation method for helmet-type PET, which would be a bottleneck to its commercialization. Therefore, we investigated appropriate performance evaluation methods for a helmet-type PET based on the NEMA NU 2-2018 standards. For those measurement methods that are not applicable to the helmet-type PET, we changed them while keeping the basic concept of the original NEMA standards. We measured spatial resolution, sensitivity, scatter fraction, count rate characteristics, accuracy of corrections for count losses and randoms, and image quality. We partially changed the measurement methods by making brain-size phantoms and by optimizing the length or the position of radioactive sources. The spatial resolution was 2.8 mm at 1-cm offset position by the filtered back-projection method. Sensitivities measured by the NEMA original setup and the proposed setup were 13.4 and 57.1 kcps/MBq. The respective values measured with our developed brain-size scatter phantom and with the conventional whole-body-size scatter phantom were: scatter fractions of 35% and 35%; peak NECRs of 25.1 kcps at 3.2 kBq/ml and 19.8 kcps at 2.6 kBq/ml ; and maximum absolute biases of 5.5% and 16.0%. The image quality was evaluated with the developed brain-size phantom, and good image quality was obtained. The helmet-type PET prototype showed high-sensitivity even with the small number of 54 detectors. The spatial resolution was better than 4.0 mm over the field-of-view. In conclusion, we proposed the performance evaluation methods for a brain-dedicated PET system with a hemispherical geometry. The proposed method could facilitate evaluation of performance characteristics of brain-dedicated PET scanners and optimization of its scanning and reconstruction parameters.

[Global Trends Survey for Targeted Radionuclide Therapy].

Radionuclide therapy has been used to help manage a range of diseases and has a role of growing importance, with an increasing impact on clinical practice globally. A survey in the field of Radionuclide therapy was conducted by reviewing 4199 science abstracts of main conference (Japanese Society of Radiological Technology, Japanese Society of Nuclear Medicine, Japanese Society of Nuclear Medicine Technology, Society of Nuclear Medicine and Molecular Imaging, European Association of Nuclear Medicine) held in 2016. This survey consisted of research content, modality for evaluation, dosimetry, radionuclide, and researcher's country. There tend to be a lot of studies related to targeted radionuclide therapy more than Japan (4%) in the United States (11%) or Europe (13%). Radiopharmaceuticals still un-approving in Japan were used in some of these studies. And many studies on dosimetry using PET or SPECT imaging were confirmed in the United States (37%) or in Europe (25%) compared with in Japan (14%). This survey has clarified the current status of Japan and global trend in the field of radionuclide therapy.

Correction method for the physical dose calculated using Clarkson integration at the center of the spread-out Bragg peak for asymmetric field in carbon-ion radiotherapy.

PURPOSE: We previously proposed a calculation method using Clarkson integration to obtain the physical dose at the center of the spread-out Bragg peak (SOBP) for a treatment beam, the measurement point of which agrees with the isocenter [Tajiri et al. Med. Phys. 2013; 40: 071733-1-5]. However, at the measurement point which does not agree with the isocenter, the physical dose calculated by this method might have a large error. For this error, we propose a correction method. MATERIALS AND METHODS: To confirm whether the error can be corrected using in-air off axis ratio (OAR), we measured the physical dose at the center of an asymmetric square field and a symmetric square field and in-air OAR. For beams of which the measurement point does not agree with the isocenter, as applied to prostate cancer patients, the physical dose calculated using Clarkson integration was corrected with in-air OAR. RESULTS: The maximum difference between the physical dose measured at the center of an asymmetric square field and the product of in-air OAR and the physical dose at the center of a symmetric square field was - 0.12%. For beams as applied to prostate cancer patients, the differences between the measured physical doses and the physical doses corrected using in-air OAR were -0.17 ± 0.23%. CONCLUSIONS: The physical dose at the measurement point which does not agree with the isocenter, can be obtained from in-air OAR at the isocenter plane and the physical dose at the center of the SOBP on the beam axis.

Calculation method using Clarkson integration for the physical dose at the center of the spread-out Bragg peak in carbon-ion radiotherapy.

PURPOSE: In broad-beam carbon-ion radiotherapy performed using the heavy-ion medical accelerator in Chiba, the number of monitor units is determined by measuring the physical dose at the center of the spread-out Bragg peak (SOBP) for the treatment beam. The total measurement time increases as the number of treatment beams increases, which hinders the treatment of an increased number of patients. Hence, Kusano et al. [Jpn. J. Med. Phys. 23(Suppl. 2), 65-68 (2003)] proposed a method to calculate the physical dose at the center of the SOBP for a treatment beam. Based on a recent study, the authors here propose a more accurate calculation method. METHODS: The authors measured the physical dose at the center of the SOBP while varying the circular field size and range-shifter thickness. The authors obtained the physical dose at the center of the SOBP for an irregularly shaped beam using Clarkson integration based on these measurements. RESULTS: The difference between the calculated and measured physical doses at the center of the SOBP varied with a change in the central angle of the sector segment. The differences between the calculated and measured physical doses at the center of the SOBP were within ± 1% for all irregularly shaped beams that were used to validate the calculation method. CONCLUSIONS: The accuracy of the proposed method depends on both the number of angular intervals used for Clarkson integration and the fineness of the basic data used for calculations: sampling numbers for the field size and thickness of the range shifter. If those parameters are properly chosen, the authors can obtain a calculated monitor unit number with high accuracy sufficient for clinical applications.