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

Mol Imaging Biol. 2020 Feb;22(1):173-180. doi: 10.1007/s11307-019-01367-w.

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.

Keywords: Alzheimer disease; Biodistribution; Cognitive decline; Human whole-body imaging; Neurofibrillary tangles; Radiation dosimetry; [18F]MK-6240.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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