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.

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.

Development of matrix metalloproteinase-targeted probes for lung inflammation detection with positron emission tomography.

As matrix metalloproteinases (MMPs), especially MMP-9 and MMP-12 are involved in the pathological processes associated with chronic obstructive pulmonary disease (COPD), we developed a novel radiofluorinated probe, 18F-IPFP, for MMPs-targeted positron emission tomography (PET). 18F-IPFP was designed by iodination of MMP inhibitor to enhance the affinity, and labelled with a compact prosthetic agent, 4-nitrophenyl 2-18F-fluoropropionate (18F-NFP). As a result, IPFP demonstrated the highest affinity toward MMP-12 (IC50 = 1.5 nM) among existing PET probes. A COPD model was employed by exposing mice to cigarette smoke and the expression levels of MMP-9 and MMP-12 were significantly increased in the lungs. Radioactivity accumulation in the lungs 90 min after administration of 18F-IPFP was 4× higher in COPD mice than normal mice, and 10× higher than in the heart, muscle, and blood. Ex vivo PET confirmed the radioactivity distribution in the tissues and autoradiography analysis demonstrated that accumulation differences in the lungs of COPD mice were 2× higher than those of normal mice. These results suggest that 18F-IPFP is a promising probe for pulmonary imaging and expected to be applied to various MMP-related diseases for early diagnosis, tracking of therapeutic effects, and new drug development in both preclinical and clinical applications.

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.

Synthesis of a new NIR fluorescent Nd complex labeling agent.

Fluorescent analysis has been widely used in biological, chemical and analytical research. A useful fluorescent labeling agent should include NIR emission, a large Stoke's shift, and good labeling ability without interfering with the pharmacological profile of the labeled compound. Thus, we planned to develop an M-AMF-DOTA(Nd) derivative composed of an NIR fluorescent moiety and a maleimide conjugating moiety as a new NIR fluorescent labeling agent which fulfills these requirements. M-AMF-DOTA(Nd) was synthesized from 4-amino-fluorescein and was conjugated with an avidin molecule (Avidin-AMF-DOTA(Nd)) through Lys-side chains by reaction with 2-iminothiolane. The fluorescent features of M-AMF-DOTA(Nd) and Avidin-AMF-DOTA(Nd) were comparatively evaluated. A binding assay of Avidin-AMF-DOTA(Nd) with D-biotin and a tumor cell-uptake study were performed to estimate the effects of conjugation on the biological and physicochemical features of the protein. M-AMF-DOTA(Nd) was obtained in 22% overall yield. M-AMF-DOTA(Nd) had a typical NIR fluorescence from the Nd ion (880 nm and 900 nm from 488 nm excitation). Avidin-AMF-DOTA(Nd) was easily synthesized and also had typical NIR fluorescence from the Nd ion without loss of fluorescent intensity. The binding affinity of Avidin-AMF-DOTA(Nd) to D-biotin was equivalent to naive avidin. Avidin-AMF-DOTA(Nd) was taken up by tumor cells in the same manner as avidin conjugated with fluorescein isothiocyanate, an established, widely used fluorescent avidin. Results from this study indicate that M-AMF-DOTA(Nd) is a potential labeling agent for routine NIR fluorescent analysis.

NIR fluorescent ytterbium compound for in vivo fluorescence molecular imaging.

We have developed a new NIR fluorescent probe based on an ytterbium(III) (E)-1-(pyridin-2-yl-diazenyl)naphthalen-2-ol (PAN) complex. This probe emits near-infrared luminescence derived from the Yb ion through excitation of the PAN moiety with visible light (lambda(ex)= 530 nm, lambda(em)= 975 nm). The results support the possible utility of the probe for in vivo fluorescence molecular imaging.

Synthesis and evaluation of a radioiodinated lumiracoxib derivative for the imaging of cyclooxygenase-2 expression.

INTRODUCTION: Despite extensive attempts to develop cyclooxygenase (COX)-2 imaging radiotracers, no suitable positron emission tomography (PET)/single photon emission computed tomography (SPECT) tracers are currently available for in vivo imaging of COX-2 expression. The aims of this study were to synthesize and evaluate a radioiodinated derivative of lumiracoxib, 2-[(2-fluoro-6-iodophenyl)-amino]-5-methylphenylacetic acid (FIMA), which is structurally distinct from other drugs in the class and has weakly acidic properties, as a SPECT tracer for imaging COX-2 expression. METHODS: The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation with hydrogen peroxide. Cell uptake characteristics of (125)I-FIMA were assessed in control and linterfero/interferon-gamma-stimulated macrophages. The biodistribution of (125)I-FIMA was determined by the ex vivo tissue counting method in rats. RESULTS: The COX-2 inhibitory potency of FIMA (IC(50)=2.46 microM) was higher than that of indomethacin (IC(50)=20.9 microM) and was comparable to lumiracoxib (IC(50)=0.77 microM) and diclofenac (IC(50)=0.98 microM). The IC(50) ratio (COX-1/COX-2=182) indicated FIMA has a high isoform selectivity for COX-2. (125)I-FIMA showed a significantly higher accumulation in COX-2 induced macrophages than in control macrophages, which decreased with nonradioactive FIMA in a concentration dependent manner. The biodistribution study showed rapid clearance of (125)I-FIMA from the blood and most organs including the liver and kidneys. No significant in vivo deiodination was observed with radioiodinated FIMA. CONCLUSIONS: FIMA showed high inhibitory potency and selectivity for COX-2. Radioiodinated FIMA showed specific accumulation into COX-2 induced macrophages, no significant in vivo deiodination and rapid blood clearance. Radioiodinated FIMA deserves further investigation as a SPECT radiopharmaceutical for imaging COX-2 expression.

Development of a novel neodymium compound for in vivo fluorescence imaging.

We developed a novel fluorescent probe that contains the neodymium(III) complex moiety and fluorescein moiety. This probe can emit long-lived near-infrared luminescence derived from a Nd ion through excitation of the fluorescein moiety with visible light (lambda(ex) = 488 nm, lambda(em) = 880 nm, lifetime = 2.3 micros). These results indicate the possibility of the probe as a candidate for in vivo fluorescence molecular imaging.

Dicopper-dioxygen complex supported by asymmetric pentapyridine dinucleating ligand.

A dicopper(I) complex supported by a novel asymmetric pentapyridine dinucleating ligand, consisting of tetradentate and tridentate metal-binding sites, has been synthesized and characterized. The dicopper(I) complex reacted with molecular oxygen at a low temperature to give an unprecedented mu-peroxo dicopper(II) complex presumably having a mu-eta1:eta2 binding mode, the spectroscopic features and the reactivity of which have been explored in detail.