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01-02-2020 | Positron Emission Tomography | Research Article

Preclinical Safety Evaluation and Human Dosimetry of [¹⁸F]MK-6240, a Novel PET Tracer for Imaging Neurofibrillary Tangles

Authors: Michel Koole, Talakad G. Lohith, John L. Valentine, Idriss Bennacef, Ruben Declercq, Tom Reynders, Kerry Riffel, Sofie Celen, Kim Serdons, Guy Bormans, Sandrine Ferry-Martin, Philippe Laroque, Abbas Walji, Eric D. Hostetler, Richard J. Briscoe, Jan de Hoon, Cyrille Sur, Koen Van Laere, Arie Struyk

Published in: Molecular Imaging and Biology | Issue 1/2020

Abstract

Purpose

[¹⁸F]MK-6240 is a selective, high-affinity positron emission tomography tracer for imaging neurofibrillary tangles, a key pathological signature that correlates with cognitive decline in Alzheimer disease. This report provides safety information from preclinical toxicology studies and first-in-human whole-body biodistribution and dosimetry studies of [¹⁸F]MK-6240 for its potential application in human brain imaging studies.

Procedures

MK-6240 was administered intravenously (IV) in a 7-day rat toxicity study at × 50, × 100, and × 1000 dose margins relative to projected highest clinical dose of 0.333 μg/kg. The IV formulation of MK-6240 for clinical use and the formulation used in the 7-day rat toxicity study was tested for hemolysis potential in human and Wistar rat whole blood. Sequential whole-body positron emission tomography scans were performed in three healthy young subjects after IV bolus injection of 180 ± 0.3 MBq [¹⁸F]MK-6240 to characterize organ biodistribution and estimate whole-body radiation exposure (effective dose).

Results

MK-6240 administered IV in a 7-day rat toxicity study did not show any test article-related changes. The no-observed-adverse-effect level in rats was ≥ 333 μg/kg/day which provides a margin 1000-fold over an anticipated maximum clinical dose of 0.333 μg/kg. Additionally, the MK-6240 formulation was not hemolytic in human or Wistar rat blood. [¹⁸F]MK-6240 activity was widely distributed to the brain and the rest of the body, with organ absorbed doses largest for the gall bladder (202 μGy/MBq). The average (±SD) effective dose was 29.4 ± 0.6 μSv/MBq, which is in the typical range for F-18 radiolabeled ligands.

Conclusions

Microdoses of [¹⁸F]MK-6240 are safe for clinical positron emission tomography imaging studies. Single IV administration of 185 MBq (5 mCi) [¹⁸F]MK-6240 is anticipated to result in a total human effective dose of 5.4 mSv and thus allows multiple positron emission tomography scans of the same subject per year.

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Title: Preclinical Safety Evaluation and Human Dosimetry of [18F]MK-6240, a Novel PET Tracer for Imaging Neurofibrillary Tangles
Authors: Michel Koole
Talakad G. Lohith
John L. Valentine
Idriss Bennacef
Ruben Declercq
Tom Reynders
Kerry Riffel
Sofie Celen
Kim Serdons
Guy Bormans
Sandrine Ferry-Martin
Philippe Laroque
Abbas Walji
Eric D. Hostetler
Richard J. Briscoe
Jan de Hoon
Cyrille Sur
Koen Van Laere
Arie Struyk
Publication date: 01-02-2020
Publisher: Springer International Publishing
Keyword: Positron Emission Tomography
Published in: Molecular Imaging and Biology / Issue 1/2020
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-019-01367-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Preclinical Safety Evaluation and Human Dosimetry of [¹⁸F]MK-6240, a Novel PET Tracer for Imaging Neurofibrillary Tangles

Abstract

Purpose

Procedures

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Procedures

Results

Conclusions

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