With Alzheimer’s Disease (AD) affecting nearly 6 million Americans and being the 6th leading cause of death in the United States, research continues to grow in hopes of understanding the development and progression of AD. Although clinical diagnosis of AD is primarily determined by observing symptoms such as cognitive decline, there has been growing interest in utilizing AD biomarkers, including positron emission tomography (PET) imaging of specific molecular targets, such as β-amyloid plaques and tau neurofibrillary tangles (NFT), in the brain to aid clinicians with diagnosis and monitoring of disease progression. While there are approved PET radiotracers for β-amyloid, there is still no FDA approved radiotracer for tau and thus work in recent years has focused on finding a suitable radioligand with high specificity for tau tangles and minimal off-target binding.
One such scientist leading the way is Dr. Tobey Betthauser at the Wisconsin Alzheimer’s Disease Research Center (ADRC). Now an Assistant Scientist at the ADRC, Dr. Betthauser’s doctorate work, under the advisement of Dr. Bradley Christian, included a recently published groundbreaking human study which demonstrated [18F]MK-6240 as a promising PET probe for imaging tau neurofibrillary tangles (NFT) in AD. In this study, Dr. Betthauser set out to characterize the kinetics, binding specificity, and spatial binding patterns of this radiotracer.
Prior to conducting the clinical study, Dr. Betthauser developed a reliable and optimized method of synthesizing [18F]MK-6240 doses using an ELIXYS automated synthesizer. Having previously used the ELIXYS system for optimization and synthesis of the radiotracer [18F]THK-5351, Dr. Betthauser was able to take the existing ELIXYS sequence for [18F]THK-5351 and simply modify a few parameters specific to the synthesis of [18F]MK-6240. Product was successfully made on the first try and after only needing a few more runs to optimize the synthesis and purification parameters, Dr. Betthauser successfully performed a series of validation runs with no issues hitting all metrics for releasing doses for human investigational use. In speaking about the versatility of the ELIXYS system to support both development and production, Dr. Betthauser states:
“The nice thing about the ELIXYS is that it’s as flexible as you need it to be. You can pause steps during development to check yields and characterize losses. It has considerably more flexibility than other systems I’ve worked on. I can take out the pause steps when I’ve locked down the routines for investigational studies. [Dr. Christian’s] lab does a lot of developmental work for first in human studies. It’s nice to have a system like [ELIXYS] which is quickly amenable to a different tracer where you don’t have to reinvent the wheel when it comes to doing the actual investigational work.”
In the human study, Dr. Betthauser evaluated [18F]MK-6240 PET imaging in 51 study participants made up of 3 young controls (ages 27-45), 33 older controls (ages 56-77), 6 unimpaired cognitive decliners, 2 showing mild cognitive impairment (MCI), and 7 with clinical diagnosis of probable AD. One key finding in the study was that individuals who were positive for β-amyloid showed [18F]MK-6240 binding consistent with NFT staging reported in neuropathology literature of tau tangles with minimal off-target binding in the brain that could preclude detection of NFTs. This directly emphasized the specificity of the [18F]MK-6240 radiotracer to detect NFTs in regions associated with early NFT stages, which may improve detection sensitivity to NFTs compared to other available tau tracers. In addition to determining high specificity and demonstrating binding patterns consistent with neuropathological staging, Dr. Betthauser also determined the kinetic profile of [18F]MK-6240 was conducive for investigating NFT in clinical research. Altogether, the results of this study were a significant step in demonstrating the utility of [18F]MK-6240 for PET imaging of tau pathology in the AD continuum.
As a follow up to Dr. Betthauser’s clinical study, a phase 2 trial is currently recruiting to assess longitudinal changes in [18F]MK-6240 PET imaging (Principal Investigator: Dr. Sterling C. Johnson in collaboration with Cerveau Technologies). This study will primarily investigate a 12-month change in [18F]MK-6240 and relationships with clinical outcome measures (MMSE, CDR, and ADAS-cog) in a sample of persons with probable AD, MCI, and similarly aged healthy volunteers. The ELIXYS, already running about 2-4 syntheses per week and having produced doses for over 240 [18F]MK-6240 human research scans, will continue to support [18F]MK-6240 studies at the University of Wisconsin. SOFIE is proud to be a part of such important research and we wish Dr. Betthauser and all those at the University of Wisconsin-Madison the best!