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Evaluation of pharmacokinetic modeling strategies for in-vivo quantification of tau with the radiotracer [18F]MK6240 in human subjects

A Correction to this article was published on 05 January 2023

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Abstract

Purpose

[18F]MK6240 was developed for PET imaging of tau aggregates, which are implicated in Alzheimer’s disease. The goal of this work was to evaluate the kinetics of [18F]MK6240 and to investigate different strategies for in-vivo quantification of tau aggregates in humans.

Methods

Thirty-five subjects, consisting of 18 healthy controls (CTRL), 11 subjects with mild cognitive impairment (MCI) and six with Alzheimer’s Disease (AD), underwent dynamic [18F]MK6240 PET scans. Arterial blood measurements were collected in 16 subjects (eight CTRLs, six MCIs and two AD) to measure whole blood and plasma concentration time courses. Radiometabolite analysis was performed on a subset of plasma samples. Various compartmental model configurations as well as the Logan and multilinear analysis (MA1) graphical methods with arterial plasma input function were tested. Simplified reference tissue methods were investigated, including Logan distribution volume ratio (DVR), multilinear reference tissue method (MRTM2), and static SUV ratio using the cerebellum as a reference region.

Results

Whole blood:plasma ratio stabilized to 0.66 ± 0.01 after 15 min. Percent parent in plasma (%PP) followed a single exponential and ranged from 0 to 10% at 90 min. [18F]MK6240 in gray matter peaked quickly (SUV > 2 at ~3 min). The preferred compartmental model was a reversible two-tissue compartment model, with the blood contribution included as a model parameter (2T4k1v). Compartmental and graphical analysis methods with arterial input functions yielded concordant results, but rapid metabolism raised challenges for blood-based quantification. MCI and AD subjects demonstrated a broad range of VT as compared to CTRL subjects. DVR from MRTM2 and Logan reference tissue methods correlated with DVR calculated indirectly from compartmental modeling, but underestimation was observed in data sets with very high binding (DVR > 3). SUVR also underestimated indirect DVR from blood-based analyses in high binding regions, although a non-linear relationship was exhibited.

Conclusions

[18F]MK6240 exhibited a wide dynamic range of uptake, with binding patterns in MCI/AD subjects consistent with neurofibrillary tau deposition patterns. Linearized reference tissue methods using an estimated average tissue-to-plasma efflux constant \( \overline{k{\prime}_2} \) and static SUVR agreed well with blood-based methods for most data sets; however, discrepancies were noted in the highest binding cases. Caution should therefore be exercised in application of simplified methods to such data sets, and in quantitative interpretation of corresponding outcomes.

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Change history

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Acknowledgements

This work was supported by the following grants: R01AG046396, S10OD018035, P41EB022544, and T32 EB005876. The authors thank Julia Scotton and Nicole DaSilva for subject preparation, scanning, and monitoring, as well as Steven Weise and Eugene Lee for their help with data management.

Funding

This study was funded by R01AG046396, S10OD018035, T32 EB005876, and P41EB022544.

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Correspondence to Nicolas J. Guehl.

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Conflict of interest

Nicolas J. Guehl declares that he has no conflict of interest. Dustin W. Wooten declares that he has no conflict of interest. Daniel L. Yokell declares that he has no conflict of interest. Sung-Hyun Moon declares that he has no conflict of interest. Maeva Dhaynaut declares that she has no conflict of interest. Samantha Katz declares that she has no conflict of interest. Kirsten A. Moody declares that she has no conflict of interest. Codi Gharagouzloo declares that he has no conflict of interest. Aurélie Kas declares that she has no conflict of interest. Keith A. Johnson declares that he has no conflict of interest. Georges El Fakhri declares that he has no conflict of interest. Marc D. Normandin declares that he has no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study

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The original online version of this article was revised: The authors regret that there is an error in their article.

The sentence:

The procedure adopted for these measurements was similar to the one described in Wooten et al. [18], except that a 62.5/37.5 sodium formate buffer/MeCN was used to backflush the catch column.

should be written as:

The procedure adopted for these measurements was similar to the one described in Wooten et al. [18], except that a 62.5/37.5 10mM sodium phosphate dibasic buffer/MeCN was used to backflush the catch column.

The original article has been corrected.

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Guehl, N.J., Wooten, D.W., Yokell, D.L. et al. Evaluation of pharmacokinetic modeling strategies for in-vivo quantification of tau with the radiotracer [18F]MK6240 in human subjects. Eur J Nucl Med Mol Imaging 46, 2099–2111 (2019). https://doi.org/10.1007/s00259-019-04419-z

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