Dosimetry and efficacy of a tau PET tracer [18F]MK-6240 in Japanese healthy elderly and patients with Alzheimer's disease.

OBJECTIVE: A new tau PET tracer [18F]MK-6240 has been developed; however, its dosimetry and pharmacokinetics have been published only for a European population. This study investigated the safety, radiation dosimetry, pharmacokinetics and biodistribution of [18F]MK-6240 in Japanese elderly subjects. Also, the pattern and extent of brain retention of [18F]MK-6240 in Japanese healthy elderly subjects and patients with Alzheimer's disease (AD) were investigated. These Japanese results were compared with previous reports on non-Japanese. METHODS: Three healthy elderly subjects and three AD patients were enrolled. Dynamic whole-body PET scans were acquired for up to 232 min after starting injection of [18F]MK-6240 (370.4 ± 27.0 MBq) for the former, while a dynamic brain scan was performed from 0 to 75 min post injection for the latter. For both groups, brain PET scans were conducted from 90 to 110 min post injection. Sequential venous blood sampling was performed to measure the radioactivity concentration in the whole blood and plasma as well as the percentages of parent [18F]MK-6240 and radioactive metabolites in plasma. Organ doses and effective doses were estimated using the OLINDA Ver.2 software. Standardized uptake value ratios (SUVRs) and distribution volume ratios (DVRs) by Logan reference tissue model (LRTM) were measured in eight brain regions using the cerebellar cortex as the reference. Blood tests, urine analysis, vital signs and electrocardiography were performed for safety assessments. RESULTS: No adverse events were observed. The highest radiation doses were received by the gallbladder (257.7 ± 74.9 µGy/MBq) and the urinary bladder (127.3 ± 11.7 µGy/MBq). The effective dose was 26.8 ± 1.4 µSv/MBq. The parent form ([18F]MK-6240) was metabolized quickly and was less than 15% by 35 min post injection. While no obvious accumulation was found in the brain of healthy subjects, focal accumulation of [18F]MK-6240 was observed in the cerebral cortex of AD patients. Regional SUVRs of the focal lesions in AD patients increased gradually over time, and the difference of SUVRs between healthy subjects and AD patients became large and stable at 90 min after injection. High correlations of SUVR and DVR were observed (p < 0.01). CONCLUSION: The findings supported safety and efficacy of [18F]MK-6240 as a tau PET tracer for Japanese populations. Even though the number of subjects was limited, the radiation dosimetry profiles, pharmacokinetics, and biodistribution of [18F]MK-6240 were consistent with those for non-Japanese populations. TRIAL REGISTRATION: Japan Pharmaceutical Information Center ID, JapicCTI-194972.

PET imaging of 11C-labeled thiamine tetrahydrofurfuryl disulfide, vitamin B1 derivative: First-in-human study.

Vitamine B1 thiamine is an essential component for glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is more absorbent compared to readily-available water-soluble thiamine salts since it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions were not clarified yet. Recently, 11C-labeled thiamine and TTFD were synthesized by our group, and their pharmacokinetics were investigated by PET imaging in normal rats. In this study, to clarify the whole body pharmacokinetics of [11C]TTFD in human healthy volunteers, we performed first-in-human PET imaging study with [11C]TTFD, along with radiation dosimetry of [11C]TTFD in humans. METHODS: Synthesis of [11C]TTFD was improved for clinical study. Dynamic whole-body PET images were acquired on three young male normal subjects after intravenous injection of [11C]TTFD. VOIs were defined for source organs on the PET images to measure time-course of [11C]TTFD uptake as percentage injected dose and the number of disintegrations for each organ. Radiation dosimetry was calculated with OLINDA/EXM. RESULTS: We succeeded in developing the improved synthetic method of [11C]TTFD for the first-in-human PET study. In the whole body imaging, uptake of [11C]TTFD by various tissues was almost plateaued at 10 min after intravenous injection, afterward gradually increased for the brain and urinary bladder (urine). %Injected dose was high in the liver, kidney, urinary bladder, heart, spine, brain, spleen, pancreas, stomach, and salivary glands, in this order. %Injected dose per gram of tissue was high also in the pituitary. By dosimetry, the effective radiation dose of [11C]TTFD calculated was 5.5 µSv/MBq (range 5.2-5.7). CONCLUSION: Novel synthetic method enabled clinical PET study with [11C]TTFD, which is a safe PET tracer with a dosimetry profile comparable to other common 11C-PET tracers. Pharmacokinetics of TTFD in the pharmacological dose and at different nutritional states could be further investigated by future quantitative PET studies. Noninvasive in vivo PET imaging for pathophysiology of thiamine-related function may provide diagnostic evidence of novel information about vitamin B1 deficiency in human tissues.

Physiological skin FDG uptake: A quantitative and regional distribution assessment using PET/MRI.

PURPOSE: To retrospectively assess the repeatability of physiological F-18 labeled fluorodeoxyglucose (FDG) uptake in the skin on positron emission tomography/magnetic resonance imaging (PET/MRI) and explore its regional distribution and relationship with sex and age. METHODS: Out of 562 examinations with normal FDG distribution on whole-body PET/MRI, 74 repeated examinations were evaluated to assess the repeatability and regional distribution of physiological skin uptake. Furthermore, 224 examinations were evaluated to compare differences in the uptake due to sex and age. Skin segmentation on PET was performed as body-surface contouring on an MR-based attenuation correction map using an off-line reconstruction software. Bland-Altman plots were created for the repeatability assessment. Kruskal-Wallis test was performed to compare the maximum standardized uptake value (SUVmax) with regional distribution, age, and sex. RESULTS: The limits of agreement for the difference in SUVmean and SUVmax of the skin were less than 30%. The highest SUVmax was observed in the face (3.09±1.04), followed by the scalp (2.07±0.53). The SUVmax in the face of boys aged 0-9 years and 10-20 years (1.33±0.64 and 2.05±1.00, respectively) and girls aged 0-9 years (0.98±0.38) was significantly lower than that of men aged ≥20 years and girls aged ≥10 years (p<0.001). In women, the SUVmax of the face (2.31±0.71) of ≥70-year-olds was significantly lower than that of 30-39-year-olds (3.83±0.82) (p<0.05). CONCLUSION: PET/MRI enabled the quantitative analysis of skin FDG uptake with repeatability. The degree of physiological FDG uptake in the skin was the highest in the face and varied between sexes. Although attention to differences in body habitus between age groups is needed, skin FDG uptake also depended on age.

Quantitative investigation of hepatobiliary transport of [11C]telmisartan in humans by PET imaging.

The pharmacokinetics of telmisartan are nonlinear within the clinical dose range. To identify the underlying mechanism of this nonlinearity, we conducted a PET study in healthy subjects using [11C]telmisartan. Eight healthy male subjects were enrolled in a 2-way crossover study. PET imaging was performed after intravenous administration of [11C]telmisartan with or without a 1-h oral predose of two 40 mg Micardis® tablets. About 60% of the injected [11C]telmisartan accumulated in the liver within 10 min after injection. With predosing of 80 mg telmisartan, the systemic elimination of [11C]telmisartan was slightly delayed, but the liver exposure started to decrease earlier and biliary excretion was greatly enhanced. Hepatic uptake clearance of the radioactivity was not changed by telmisartan predosing, whereas the biliary clearance of radioactivity from the liver was significantly increased. Thus, the alteration in the pharmacokinetics of the radioactivity could not be explained simply by the saturation of hepatic uptake. Therefore, other mechanisms, such as the saturation of intracellular binding of telmisartan and/or its glucuronide, and the glucuronidation of telmisartan by uridine 5'-diphospho-glucuronosyltransferases, should be considered. This is the first reported human PET study using [11C]telmisartan, the results of which can assist understanding of the hepatobiliary transport of telmisartan in humans.

Voxel-based statistical analysis and quantification of amyloid PET in the Japanese Alzheimer's disease neuroimaging initiative (J-ADNI) multi-center study.

BACKGROUND: Amyloid PET plays a vital role in detecting the accumulation of in vivo amyloid-ß (Aß). The quantification of Aß accumulation has been widely performed using the region of interest (ROI)-based mean cortical standardized uptake value ratio (mcSUVR). However, voxel-based statistical analysis has not been well studied. The purpose of this study was to examine the feasibility of analyzing amyloid PET scans by voxel-based statistical analysis. The results were then compared to those with the ROI-based mcSUVR. In total, 166 subjects who underwent 11C-PiB PET in the J-ADNI multi-center study were analyzed. Additionally, 18 Aß-negative images were collected from other studies to form a normal database. The PET images were spatially normalized to the standard space using an adaptive template method without MRI. The mcSUVR was measured using a pre-defined ROI. Voxel-wise Z-scores within the ROI were calculated using the normal database, after which Z-score maps were generated. A receiver operating characteristic (ROC) analysis was performed to evaluate whether Z-sum (sum of the Z-score) and mcSUVR could be used to classify the scans into positive and negative using the central visual read as the reference standard. PET scans that were equivocal were regarded as positive. RESULTS: Sensitivity and specificity were respectively 90.8% and 100% by Z-sum and 91.8% and 98.5% by mcSUVR. Most of the equivocal scans were subsequently classified by both Z-sum and mcSUVR as false negatives. Z-score maps correctly delineated abnormal Aß accumulation over the same regions as the visual read. CONCLUSIONS: We examined the usefulness of voxel-based statistical analysis for amyloid PET. This method provides objective Z-score maps and Z-sum values, which were observed to be helpful as an adjunct to visual interpretation especially for cases with mild or limited Aß accumulation. This approach could improve the Aß detection sensitivity, reduce inter-reader variability, and allow for detailed monitoring of Aß deposition. TRIAL REGISTRATION: The number of the J-ADNI study is UMIN000001374.

Technical Considerations on Scanning and Image Analysis for Amyloid PET in Dementia.

Brain imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET), can provide essential and objective information for the early and differential diagnosis of dementia. Amyloid PET is especially useful to evaluate the amyloid-ß pathological process as a biomarker of Alzheimer's disease. This article reviews critical points about technical considerations on the scanning and image analysis methods for amyloid PET. Each amyloid PET agent has its own proper administration instructions and recommended uptake time, scan duration, and the method of image display and interpretation. In addition, we have introduced general scanning information, including subject positioning, reconstruction parameters, and quantitative and statistical image analysis. We believe that this article could make amyloid PET a more reliable tool in clinical study and practice.

A revisit to quantitative PET with 18F-FDOPA of high specific activity using a high-resolution condition in view of application to regenerative therapy.

OBJECTIVE: With the advent of regenerative/cell therapy for Parkinson's disease (PD), 18F-FDOPA has drawn new attention as a biomarker of the therapeutic that cannot be evaluated with radiopharmaceuticals for dopamine transporter. Since most previous 18F-FDOPA PET studies were carried out many years ago with a PET scanner of lower resolution and with 18F-FDOPA of low specific activity synthesized from 18F-F2, we used a newer PET/CT scanner with a high-resolution condition and 18F-FDOPA synthesized from 18F-F- to re-evaluate this technique on normal subjects and patients with PD, together with D2 receptor imaging with 11C-raclopride (RAC). METHODS: PET scans were carried out with 18F-FDOPA for 120 min and with 11C-RAC for 60 min on 10 patients clinically diagnosed with PD and on 10 normal control subjects. Image reconstruction parameters were optimized with phantom experiments. Graphical analysis and the ratio method for the late-phase images were performed to quantify the striatal uptakes. RESULTS: The specific activity of 18F-FDOPA was as high as 4000 MBq/nmol. We empirically determined appropriate reconstruction parameters to obtain high-resolution PET images with enough quantitative accuracy. Both 18F-FDOPA and 11C-RAC PET showed higher uptake values on normal subjects than those of the previous studies probably due to high-resolution. Quantified ratio values strongly correlated with the graphical values for both tracers. Furthermore, 18F-FDOPA uptake in the substantia nigra was clearly visualized in most subjects. CONCLUSION: Quantitative 18F-FDOPA and 11C-RAC PET scans using a high-resolution condition are considered to provide essential information for regenerative dopaminergic therapy. Furthermore, the ratio analysis for the late-phase PET scans with 18F-FDOPA and 11C-RAC enhances the clinical utility of these dopaminergic PET as imaging biomarkers of PD.

Exploratory human PET study of the effectiveness of (11)C-ketoprofen methyl ester, a potential biomarker of neuroinflammatory processes in Alzheimer's disease.

INTRODUCTION: Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease (AD). As a biomarker of neuroinflammatory processes, we designed (11)C-labeled ketoprofen methyl ester ([(11)C]KTP-Me) to increase the blood-brain barrier permeability of ketoprofen (KTP), a selective cyclooxygenase-1 (COX-1) inhibitor. Animal studies indicated that [(11)C]KTP-Me enters the brain and accumulates in activated microglia of inflammatory lesions. In a first-in-human study, we reported that [(11)C]KTP-Me is a safe positron emission tomography (PET) tracer and enters the brain; the radioactivity is washed out from normal cerebral tissue. Here we explored the efficacy of [(11)C]KTP-Me as a diagnostic biomarker of neuroinflammatory processes in AD. METHODS: [(11)C]KTP-Me was synthesized by rapid C-[(11)C]methylation of [(11)C]CH3I and the corresponding arylacetate precursor. Nine subjects (four healthy subjects, two Pittsburgh compound-B (PiB)-positive patients with mild cognitive impairment (MCI), and three PiB-positive AD patients) underwent a dynamic brain PET scan for 70min after injection. We evaluated differences in cortical retention and washout rate in the brain between healthy subjects and MCI/AD patients. RESULTS: A brain distribution pattern reflecting blood flow in the early-phase image was seen in both healthy subjects and MCI/AD patients. Cortical activity gradually cleared in all groups. However, we observed no obvious difference in the washout rate between healthy subjects and MCI/AD patients or between MCI and AD patients. CONCLUSIONS: [(11)C]KTP-Me cannot be useful as a potential diagnostic biomarker for MCI/AD. Further improvements in binding affinity and specificity, etc., are needed to be a diagnostic biomarker of neuroinflammation in AD. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: [(11)C]KTP-Me is a new tracer that targets COX-1. [(11)C]KTP-Me is expected to be a diagnostic biomarker of neuroinflammation in AD in the future. The effectiveness was limited in a small number of AD patients. Therefore, further studies are needed to clarify the usefulness of [(11)C]KTP-Me.

Optimization of image reconstruction conditions with phantoms for brain FDG and amyloid PET imaging.

OBJECTIVES: The purpose of this study was to optimize image reconstruction conditions for brain (18)F-FDG, (11)C-PiB, (18)F-florbetapir and (18)F-flutemetamol PET imaging with Discovery-690 PET/CT for diagnosis and research on Alzheimer's disease (AD) based on the standard imaging protocols and phantom test procedures and criteria published by the Japanese society of nuclear medicine (JSNM). METHODS: A Hoffman 3D brain phantom and a cylindrical pool phantom were scanned according to the JSNM procedure, and the reconstruction conditions (iteration, subset, post-filter) were optimized so that the images satisfy the JSNM criteria regarding spatial resolution (FWHM ≤ 8 mm) and gray/white matter contrast (%contrast ≥ 55%) on the Hoffman phantom and uniformity (SD of small ROIs ≤ 0.0249) and image noise (coefficient of variation ≤ 15 %) on the pool phantom. Human images were acquired with (18)F-FDG (15-min scan starting at 30 min post-injection [p.i.] of 185 MBq), (11)C-PiB (20-min scan starting at 50 min p.i. of 555 MBq), (18)F-florbetapir (10-min scan starting at 50 min p.i. of 370 MBq) and (18)F-flutemetamol (30-min scan starting at 90 min p.i. of 185 MBq) on 1 or 2 subjects for each tracer and reconstructed with thus determined conditions to evaluate the image quality visually. The effect of reconstruction parameters on the standardized uptake value ratio (SUVR) was also evaluated on 5 amyloid-positive and 5 amyloid-negative PiB images. RESULTS: A sufficient image quality was obtained at an iterative update (product of iteration and subset) of 64 for (18)F-FDG. The same reconstruction parameters with an additional Gaussian filter of 5 mm FWHM was optimal for (11)C-PiB, (18)F-florbetapir and (18)F-flutemetamol to achieve the phantom criteria. Those optimal reconstruction conditions were confirmed with human images. The SUVR value was stable over a wide range of iterative updates around the optimal parameters both for positive and negative amyloid images. CONCLUSIONS: Optimal image reconstruction conditions were determined for brain (18)F-FDG and amyloid PET imaging with Discovery-690 PET/CT for diagnosis and research on AD based on the JSNM phantom criteria. This supports feasibility of the phantom criteria for standardization and harmonization of brain (18)F-FDG and amyloid PET for multicenter studies.

[Harmonization of Standardized Uptake Value among Different Generation PET/ CT Cameras Based on a Phantom Experiment -Utility of SUV(peak)].

Standardized uptake value (SUV) has been widely used as a semi-quantitative metric of uptake in FDGPET/ CT for diagnosis of malignant tumors and evaluation of tumor therapies. However, the SUV depends on various factors including PET/CT scanner specifications and reconstruction parameters. The purpose of this study is to harmonize the SUV among two PET/CT models of different generation: two units of Discovery ST Elite Performance(DSTEP) and Discovery 690 (D690) PET/CT scanners. The NEMA body phantom filled with 18F solution was scanned for 30 minutes in list-mode. The D690 PET images were reconstructed with OSEM, OSEM+TOF, and OSEM+PSF. Gaussian post-filters of 4-9 mm FWHM were applied to find the parameters that provides harmonized SUV. We determined the SUV-harmonized parameter for each reconstruction algorithm. Then, the 10 PET images simulating clinical scan conditions were respectively generated to evaluate the bias and variability of SUV(max) and SUV(peak). The SUV(max) strongly depended not only on spatial resolution but also on image noise. On the other hand, the SUV(peak) was a robust metric to image noise level. TOF improved the variability of SUV(max) and SUV(peak). Thus, we were able to harmonize the spatial resolution using SUV(peak) based on the phantom study. Because SUV(max) was also strongly affected by image noise, sufficient count statistics is essential for SUV(max) harmonization. We recommended that TOF reconstruction and SUV(peak) metric should be used to harmonize SUV.

Influence of Statistical Fluctuation on Reproducibility and Accuracy of SUVmax and SUVpeak: A Phantom Study.

UNLABELLED: Standardized uptake values (SUVs) have been widely used in the diagnosis of malignant tumors and in clinical trials of tumor therapies as semiquantitative metrics of tumor (18)F-FDG uptake. However, SUVs for small lesions are liable to errors due to partial-volume effect and statistical noise. The purpose of this study was to evaluate the reproducibility and accuracy of maximum and peak SUV (SUVmax and SUVpeak, respectively) of small lesions in phantom experiments. METHODS: We used a body phantom with 6 spheres in a quarter warm background. The PET data were acquired for 1,800 s in list-mode, from which data were extracted to generate 15 PET images for each of the 60-, 90-, 120-, 150-, and 180-s scanning times. The SUVmax and SUVpeak of the hot spheres in the 1,800-s scan were used as a reference (SUVref,max and SUVref,peak). Coefficients of variation for both SUVmax and SUVpeak in hot spheres (CVmax and CVpeak) were calculated to evaluate the variability of the SUVs. On the other hand, percentage differences between SUVmax and SUVref,max and between SUVpeak and SUVref,peak were calculated for evaluation of the accuracy of SUV. We additionally examined the coefficients of variation of background activity and the percentage background variability as parameters for the physical assessment of image quality. RESULTS: Visibility of a 10-mm-diameter hot sphere was considerably different among scan frames. The CVmax and CVpeak increased as the sphere size became smaller and as the acquisition time became shorter. SUVmax was generally overestimated as the scan time shortened and the sphere size increased. The SUVmax and SUVpeak of a 37-mm-diameter sphere for 60-s scans had average positive biases of 28.3% and 4.4%, compared with the reference. CONCLUSION: SUVmax was variable and overestimated as the scan time decreased and the sphere size increased. In contrast, SUVpeak was a more robust and accurate metric than SUVmax. The measurements of SUVpeak (or SUVpeak normalized to lean body mass) in addition to SUVmax are desirable for reproducible and accurate quantification in clinical situations.

Human whole-body biodistribution and dosimetry of a new PET tracer, [(11)C]ketoprofen methyl ester, for imagings of neuroinflammation.

INTRODUCTION: Neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease and other brain disorders, and nonsteroidal anti-inflammatory drugs (NSAIDs) are considered therapeutic candidates. As a biomarker of neuroinflammatory processes, (11)C-labeled ketoprofen methyl ester ([(11)C]KTP-Me) was designed to allow cerebral penetration of ketoprofen (KTP), an active form of a selective cyclooxygenase-1 inhibitor that acts as an NSAID. Rat neuroinflammation models indicate that [(11)C]KTP-Me enters the brain and is retained in inflammatory lesions, accumulating in activated microglia. [(11)C]KTP-Me is washed out from normal tissues, leading to the present first-in-human exploratory study. METHODS: [(11)C]KTP-Me was synthesized by rapid C-[(11)C]methylation of [(11)C]CH3I and the corresponding arylacetate precursor, purified with high-performance liquid chromatography, and prepared as an injectable solution including PEG400, providing radiochemical purity of >99% and specific activity of >25GBq/µmol at injection. Six young healthy male humans were injected with [(11)C]KTP-Me and scanned with PET camera to determine the early-phase brain time course followed by three whole-body scans starting 8, 20, and 40 min post-injection, together with sequential blood sampling and labeled metabolite analysis. RESULTS: No adverse effects were observed during PET scanning after [(11)C]KTP-Me injection. [(11)C]KTP-Me was rapidly metabolized to (11)C-labeled ketoprofen ([(11)C]KTP) within 2-3 min and was gradually cleared from blood. The radioactivity entered the brain with an average peak cortical SUV of 1.5 at 2 min. The cortical activity was gradually washed out. Whole-body images indicated that the urinary bladder was the major excretory pathway. The organ with the highest radiation dose was the urinary bladder (average dose of 41µGy/MBq, respectively). The mean effective dose was 4.7µSv/MBq, which was comparable to other (11)C-labeled radiopharmaceuticals. CONCLUSION: [(11)C]KTP-Me demonstrated a favorable dosimetry, biodistribution, and safety profile. [(11)C]KTP-Me entered the human brain, and the radioactivity was washed out from cerebral tissue. These data warrant further exploratory studies on patients with neuroinflammation.