Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Ohnishi A

PROVIDER: S-EPMC9902412 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Ohnishi Akihito A Akamatsu Go G Ikari Yasuhiko Y Nishida Hiroyuki H Shimizu Keiji K Matsumoto Keiichi K Aita Kazuki K Sasaki Masahiro M Yamamoto Yasuji Y Yamane Tomohiko T Senda Michio M

Annals of nuclear medicine 20221121 2

<h4>Objective</h4>A new tau PET tracer [<sup>18</sup>F]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 [<sup>18</sup>F]MK-6240 in Japanese elderly subjects. Also, the pattern and extent of brain retention of [<sup>18</sup>F]MK-6240 in Japanese healthy elderly subjects and patients with Alzheimer's disease (AD) were investigat ...[more]

PMID: 36411357

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Project description:Background[18F]MK-6240 is a PET tracer with sub-nanomolar affinity for neurofibrillary tangles. Therefore, tau quantification is possible with [18F]MK-6240 PET/CT scans, and it can be used for assessment of Alzheimer's disease. However, long acquisition scans are required to provide fully quantitative estimates of pharmacokinetic parameters. Therefore, on the present study, dual-time-window (DTW) acquisitions was simulated to reduce PET/CT acquisition time, while taking into consideration perfusion changes and possible scanning protocol non-compliance. To that end, time activity curves (TACs) representing a 120-min acquisition (TAC120) were simulated using a two-tissue compartment model with metabolite corrected arterial input function from 90-min dynamic [18F]MK-6240 PET scans of three healthy control subjects and five subjects with mild cognitive impairment or Alzheimer's disease. Therefore, TACs corresponding to different levels of specific binding were generated and then various perfusion changes were simulated. Next, DTW acquisitions were simulated consisting of an acquisition starting at tracer injection, a break and a second acquisition starting at 90 min post-injection. Finally, non-compliance with the PET/CT scanning protocol were simulated to assess its impact on quantification. All TACs were quantified using reference Logan's distribution volume ratio (DVR) and standardized uptake value ratio (SUVR90) using the cerebellar cortex as reference region.ResultsIt was found that DVR from a DTW protocol with a 60-min break between two 30-min dynamic scans closely approximates the DVR from the uninterrupted TAC120, with a regional bias smaller than 2.5%. Moreover, SUVR90 estimates were more susceptible (regional bias ≤ 19%) to changes in perfusion compared to DVR from a DTW TAC (regional bias ≤ 10%). Similarly, SUVR90 was affected by late-time scanning protocol delays reaching an increase of 8% for a 20-min delay, while DVR was not affected (regional bias < 1.5%) by DTW protocol non-compliance.ConclusionsTherefore, such DTW protocol has the potential to increase patient comfort and throughput without compromising quantitative accuracy and is more reliable against SUVR in terms of perfusion changes and protocol deviations, which could prove beneficial for drug effect assessment and patient follow-up using longitudinal [18F]MK-6240 PET imaging.

Project description:Purpose[18F]3F4AP is a novel PET radiotracer that targets voltage-gated potassium (K+) channels and has shown promise for imaging demyelinated lesions in animal models of neurological diseases. This study aimed to evaluate the biodistribution, safety, and radiation dosimetry of [18F]3F4AP in healthy human volunteers.MethodsFour healthy volunteers (2 females) underwent a 4-h dynamic PET scan from the cranial vertex to mid-thigh using multiple bed positions after administration of 368 ± 17.9 MBq (9.94 ± 0.48 mCi) of [18F]3F4AP. Volumes of interest for relevant organs were manually drawn guided by the CT, and PET images and time-activity curves (TACs) were extracted. Radiation dosimetry was estimated from the integrated TACs using OLINDA software. Safety assessments included measuring vital signs immediately before and after the scan, monitoring for adverse events, and obtaining a comprehensive metabolic panel and electrocardiogram within 30 days before and after the scan.Results[18F]3F4AP distributed throughout the body with the highest levels of activity in the kidneys, urinary bladder, stomach, liver, spleen, and brain and with low accumulation in muscle and fat. The tracer cleared quickly from circulation and from most organs. The clearance of the tracer was noticeably faster than previously reported in nonhuman primates (NHPs). The average effective dose (ED) across all subjects was 12.1 ± 2.2 μSv/MBq, which is lower than the estimated ED from the NHP studies (21.6 ± 0.6 μSv/MBq) as well as the ED of other fluorine-18 radiotracers such as [18F]FDG (~ 20 μSv/MBq). No differences in ED between males and females were observed. No substantial changes in safety assessments or adverse events were recorded.ConclusionThe biodistribution and radiation dosimetry of [18F]3F4AP in humans are reported for the first time. The average total ED across four subjects was lower than most 18F-labeled PET tracers. The tracer and study procedures were well tolerated, and no adverse events occurred.

Project description:Background: The goal of this study was to report a fully automated radiosynthetic procedure of a novel tau tracer [18F]-S16 and its safety, biodistribution, and dosimetry in healthy volunteers as well as the potential utility of [18F]-S16 positron emission tomography (PET) in Alzheimer's disease (AD). Methods: The automated radiosynthesis of [18F]-S16 was performed on a GE Tracerlab FX2 N module. For the biodistribution and dosimetry study, healthy volunteers underwent a series of PET scans acquired at 10, 60, 120, and 240 min post-injection. The biodistribution and safety were assessed. For the AD study, both AD and healthy controls (HCs) underwent dynamic [18F]-S16 and static [18F]-FDG PET imaging. [18F]-S16 binding was assessed quantitatively using standardized uptake value ratios (SUVRs) measured at different regions of interest (ROIs). [18F]-S16 SUVRs were compared between the AD patients and HCs using the Mann-Whitney U-test. In AD patients with all cortical ROIs, Spearman rank-correlation analysis was used to calculate the voxel-wise correlations between [18F]-S16 and [18F]-FDG. Results: The automated radiosynthesis of [18F]-S16 was finished within 45 min, with a radiochemical yield of 30 ± 5% (n = 8, non-decay-corrected). The radiochemical purity was greater than 98%, and the specific activity was calculated to be 1,047 ± 450 GBq/μmol (n = 5), and [18F]-S16 was stable in vitro. In the healthy volunteer study, no adverse effect was observed within 24 h post-injection, and no defluorination was observed in vivo. The radiotracer could pass through the blood-brain barrier easily and was rapidly cleared from the circulation and excreted through the hepatic system. The whole-body mean effective dose was 15.3 ± 0.3 μSv/MBq. In AD patients, [18F]-S16 accumulation was identified as involving the parietal, temporal, precuneus, posterior cingulate, and frontal lobes. No specific [18F]-S16 cerebral uptake was identified in HCs. The SUVR of AD patients was significantly higher than that of HCs. No specific binding uptake was found in the choroid plexus, venous sinus, and white matter. A significant correlation was found between [18F]-S16 binding and hypometabolism across neocortical regions. Conclusion: [18F]-S16 could be synthesized automatically, and it showed favorable biodistribution and safety in humans. [18F]-S16 PET indicated a high image quality for imaging tau deposition in AD and distinguishing AD from HCs.

Project description:PurposeThe tau tracer [18F]AV1451, also known as flortaucipir, is a promising ligand for imaging tau accumulation in Alzheimer's disease (AD). Most of the previous studies have quantified tau load using standardized uptake value ratios (SUVr) derived from a static [18F]AV1451 scan. SUVr may, however, be flow dependent and, especially for longitudinal studies, should be validated against a fully quantitative approach. The objective of this study was to identify the optimal tracer kinetic model for measuring tau load using [18F]AV1451.ProceduresFollowing intravenous injection of 225 ± 16 MBq [18F]AV1451, 130 min dynamic PET scans were performed in five biomarker confirmed AD patients and five controls. Arterial blood sampling was performed to obtain a metabolite-corrected plasma input function. Next, regional time-activity curves were generated using PVElab software. These curves were analysed using several pharmacokinetic models.ResultsThe reversible single tissue compartment model (1T2k_VB) was the preferred model for all but one control. For AD patients, however, model preference shifted towards a reversible two tissue compartmental model (2T4k_VB). The simplified reference tissue model (SRTM) derived binding potential (BPND) showed good correlation (AD: r 2 = 0.87, slope = 1.06; controls: r 2 = 0.87, slope = 0.86) with indirect plasma input binding (distribution volume ratio-1). Standardized uptake value ratios (80-100 min) correlated well with DVR (r 2 = 0.93, slope = 1.07) and SRTM-derived BPND (r 2 = 0.84, slope = 0.95). In addition, regional differences in tracer binding between subject groups in different tau-specific regions were observed.ConclusionsModel preference of [18F]AV1451 appears to depend on subject status and, in particular, VT. The relationship between model preference and VT suggests that (higher) tau load may be reflected by a second tissue compartment. Nevertheless, consistent results can be obtained using a 2T4k_VB model. In addition, SRTM can be used to derive BPND.

Dataset Information

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

Objective

Methods

Results

Conclusion

Trial registration

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Objective

Methods

Results

Conclusion

Trial registration

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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