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

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.

• 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
• Journal: Molecular imaging and biology (Mol Imaging Biol) Vol. 22 Issue 1 Pg. 173-180 (02 2020) ISSN: 1860-2002 [Electronic] United States
• PMID: 31111397 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fluorine Radioisotopes
• Isoquinolines
• MK-6240
• Radiopharmaceuticals
• Fluorine-18

Topics

• Alzheimer Disease (diagnostic imaging, metabolism, pathology)
• Animals
• Female
• Fluorine Radioisotopes (pharmacokinetics)
• Healthy Volunteers
• Humans
• Isoquinolines (pharmacokinetics)
• Male
• Neurofibrillary Tangles (metabolism, pathology)
• Patient Safety
• Positron Emission Tomography Computed Tomography (methods)
• Radiometry (methods)
• Radiopharmaceuticals (pharmacokinetics)
• Rats
• Rats, Wistar
• Tissue Distribution
• Whole Body Imaging (methods)