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

• Published in: Molecular imaging and biology Vol. 22; no. 1; pp. 173 - 180
• Main Authors: Koole, Michel, Lohith, Talakad G., Valentine, John L., Bennacef, Idriss, Declercq, Ruben, Reynders, Tom, Riffel, Kerry, Celen, Sofie, Serdons, Kim, Bormans, Guy, Ferry-Martin, Sandrine, Laroque, Philippe, Walji, Abbas, Hostetler, Eric D., Briscoe, Richard J., de Hoon, Jan, Sur, Cyrille, Van Laere, Koen, Struyk, Arie
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.02.2020; Springer Nature B.V
• Subjects: Alzheimer Disease - diagnostic imaging; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Animals; Blood; Brain; Cognitive ability; Dosimeters; Dosimetry; Drug delivery systems; Emission analysis; Female; Fluorine isotopes; Fluorine Radioisotopes - pharmacokinetics; Gallbladder; Healthy Volunteers; Humans; Imaging; Isoquinolines - pharmacokinetics; Male; Medical imaging; Medicine; Medicine & Public Health; Neurodegenerative diseases; Neurofibrillary tangles; Neurofibrillary Tangles - metabolism; Neurofibrillary Tangles - pathology; Neuroimaging; Patient Safety; Positron emission; Positron emission tomography; Positron Emission Tomography Computed Tomography - methods; Radiation; Radiation dosage; Radiation effects; Radiology; Radiometry - methods; Radiopharmaceuticals - pharmacokinetics; Rats; Rats, Wistar; Research Article; Safety; Studies; Tissue Distribution; Tomography; Toxicity; Toxicity testing; Toxicology; Whole Body Imaging - methods; Cognitive decline; F]MK-6240; Neurofibrillary tangles; Human whole-body imaging; Alzheimer disease; Radiation dosimetry; [; Biodistribution; [18F]MK-6240
• ISSN: 1536-1632; 1860-2002
• DOI: 10.1007/s11307-019-01367-w

Purpose [ 18 F]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 [ 18 F]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 [ 18 F]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. [ 18 F]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 [ 18 F]MK-6240 are safe for clinical positron emission tomography imaging studies. Single IV administration of 185 MBq (5 mCi) [ 18 F]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.