Preclinical Characterization of ¹⁸F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles

Abstract

A PET tracer is desired to help guide the discovery and development of disease-modifying therapeutics for neurodegenerative diseases characterized by neurofibrillary tangles (NFTs), the predominant tau pathology in Alzheimer disease (AD). We describe the preclinical characterization of the NFT PET tracer 18 F-MK-6240. Methods: In vitro binding studies were conducted with 3 H-MK-6240 in tissue slices and homogenates from cognitively normal and AD human brain donors to evaluate tracer affinity and selectivity for NFTs. Immunohistochemistry for phosphorylated tau was performed on human brain slices for comparison with 3 H-MK-6240 binding patterns on adjacent brain slices. PET studies were performed with 18 F-MK-6240 in monkeys to evaluate tracer kinetics and distribution in the brain. 18 F-MK-6240 monkey PET studies were conducted after dosing with unlabeled MK-6240 to evaluate tracer binding selectivity in vivo. Results: The 3 H-MK-6240 binding pattern was consistent with the distribution of phosphorylated tau in human AD brain slices. 3 H-MK-6240 bound with high affinity to human AD brain cortex homogenates containing abundant NFTs but bound poorly to amyloid plaque-rich, NFT-poor AD brain homogenates. 3 H-MK-6240 showed no displaceable binding in the subcortical regions of human AD brain slices and in the hippocampus/entorhinal cortex of non-AD human brain homogenates. In monkey PET studies, 18 F-MK-6240 displayed rapid and homogeneous distribution in the brain. The 18 F-MK-6240 volume of distribution stabilized rapidly, indicating favorable tracer kinetics. No displaceable binding was observed in self-block studies in rhesus monkeys, which do not natively express NFTs. Moderate defluorination was observed as skull uptake. Conclusion: 18 F-MK-6240 is a promising PET tracer for the in vivo quantification of NFTs in AD patients. Cur rently, the clinical evaluation of disease-modifying therapies for Alzheimer disease (AD) requires large, resourceintensive clinical trials focused on measuring cognitive endpoints, which are highly variable. A biomarker that could be used early in clinical development to build confidence in the ability of a therapeutic mechanism to modify disease progression would provide a valuable bridge to investment in a large efficacy study once adequate pharmacokinetics, safety, and tolerability have been established. Biomarkers currently in use (e.g., volumetric MRI, amyloid plaque PET, cerebrospinal fluid measures of amyloid-b and tau) either do not directly inform on modification of disease pathology (volumetric MRI) or do not correlate strongly enough with cognitive decline to measure therapeutic response (amyloid plaque PET and cerebrospinal fluid measures) (1,2). Therefore, there is an unmet need for sensitive biomarkers that quantify early pathologic changes and correlate closely to disease progression and clinical outcomes.Histologic analysis of brains from human autopsy cases have shown that the density and distribution of neurofibrillary tangles (NFTs) correlate with cognitive decline ...

In Vivo Comparison of Tau Radioligands 18F-THK-5351 and 18F-THK-5317

“…Beyond regions associated with tau pathology, high suspected off-target binding was observed in all subjects (figure 5), including cognitively stable individuals in their mid-50’s, in the thalamus, striatum, substantia nigra and periaqueductal GM. This binding is similar to reports of suspected off-target binding for tau PET ligand T807, which has been proposed to bind to MAO-A and neuromelanin, albeit with a wide range of reported affinities for these binding sites in the literature(12,14,29,37). Further characterization of tau ligand binding profiles including arterial blood sampling and postmortem correlates is needed to determine the potential limitations to detect AD tau in vivo .…”

“…Following the success of amyloid PET, radioligands are being investigated for pathologic tau imaging(11-14). The THK series developed by investigators at Tohoku University have potential for in vivo detection of AD tau.…”

18F-Flortaucipir Binding in Choroid Plexus: Related to Race and Hippocampus Signal

“…In vivo and autoradiography studies suggest that FTP PET may be useful for detection of PHF-tau aggregates in AD; however, both have also identified other tracer binding substrates that appear not to be tau-related, so called “off-target” binding [7, 8, 10]. FTP PET signal is particularly prominent within the choroid plexus (CP) among a subset of individuals [5], but the substrate of this binding has not been established.…”

“…The CP of the lateral ventricles contain several materials that could possibly bind to FTP, including melanin [13], calcification/mineralization [14], Biondi rings [15, 16], and iron deposits [17]. Monoamine oxidase A has also been cited as a source of off-target binding [10, 18]. We hypothesized that if FTP were binding to melanocytes in CP, then CP FTP PET measures would be elevated in Black/African American (B/AA) participants compared to White (W) participants.…”

Is Tau Imaging More Than Just Upside-Down 18F-FDG Imaging?

“…The most widely used tracers are 18 F-AV-1451, 18 F-THK5351, and 11 C-PBB3 (8,9). More recently, tracers such as 18 F-MK-6240, 18 F-RO6958948, 18 F-PI-2620, and 18 F-JNJ64349311 have been introduced, and further compounds are under evaluation (10)(11)(12). Although some of these compounds are already being tested in clinical trials (up to phase 3), all of the available tracers can currently still be considered in an exploratory stage and the available literature is still limited.…”