Tau Radioligand Imaging for Alzheimer's Disease
Palo Alto (17 mi)Overseen byDean F Wong
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Washington University School of Medicine
No Placebo Group
Trial Summary
What is the purpose of this trial?This is an open label study to compare three new generation TAU radioligands, 18F-RO948 (formerly known as 18F-6958948), 18F-MK6240, and \[18F\]GTP1for imaging of taupathy and demonstrate their absence of off-target binding in patients with Alzheimer disease (AD) and older healthy controls (OC). The study will directly compare AD and OC with these three next-generation TAU radioligands and compare each of them with historical data of the current most widely used first generation radioligand, 18F-AV1451. Upto38 (30 AD (Amyloid +)and 8 OC (Amyloid -), matched for age and sex with A+ subjects) male and female subjects aged 50-100 will be enrolled in this study protocol: up to 8 for Cohort 1, up to 8 for Cohort 2, and up to 22 for Cohort 3. The study consists of three cohorts: Cohort 1: Up to8 AD subjects (A+; CDR 0.5 and 1)will receive two PET scans in random order, with receiving either18F-RO948 or18F-MK6240 at the first scan. A third scan with 18F-GTP1is possible, depending on timing and radiotracer availability Cohort 2:Up to8 OC (A-; CDR=0)subjects will receive two PET scans in random order, with receiving either18F-RO948or 18F-MK6240 at the first scan. A third scan with 18F-GTP1is possible, depending on timing and radiotracer availability Cohort 3:Up to 22 (A+; CDR = 0, .5 and 1) subjects will receive three PET scans in random order, with receiving 18F-RO94818F-MK6240 or18F-GTP1at the first scan. Efforts will be made to include about 1/3 CDR = 0, 1/3 CDR .5, and 1/3 CDR 1 in Cohort 3.
What data supports the idea that Tau Radioligand Imaging for Alzheimer's Disease is an effective treatment?The available research shows that Tau Radioligand Imaging, specifically using 18F-RO-948, is promising for identifying tau build-up in the brains of Alzheimer's patients. This imaging method can effectively distinguish between patients with mild Alzheimer's and healthy individuals, indicating its potential usefulness in diagnosing and monitoring the disease. However, the research does not provide evidence that this imaging technique is an effective treatment for Alzheimer's, as it is primarily used for diagnostic purposes rather than as a therapeutic intervention.12357
Do I need to stop my current medications for the trial?The trial requires that your current medications be stable for at least 4 weeks before starting and remain unchanged during the trial. So, you don't need to stop them, but you can't change them either.
Is the treatment in the trial 'Tau Radioligand Imaging for Alzheimer's Disease' a promising treatment?Yes, the treatment is promising because it uses special imaging techniques to detect tau proteins in the brain, which are linked to Alzheimer's disease. This can help in early and accurate diagnosis, potentially leading to better outcomes for patients.12457
What safety data exists for tau radioligand imaging in Alzheimer's disease?The safety data for tau radioligand imaging, specifically for [18F]MK-6240 and 18F-RO-948, includes preclinical toxicology studies and first-in-human dosimetry studies. [18F]MK-6240 has undergone preclinical safety evaluations and human dosimetry studies, indicating its potential application in human brain imaging. The studies suggest that these radioligands are promising for imaging tau aggregates in Alzheimer's disease, with good brain entry, rapid washout, and favorable metabolism patterns observed in preclinical evaluations.25678
Eligibility Criteria
This trial is for men and women aged 50-100 with probable Alzheimer's Disease (AD) who can undergo PET scans. AD participants must have a positive amyloid test, while older controls need normal cognitive function. Women of childbearing age must use contraception, and all subjects should be able to consent or have a representative do so.Inclusion Criteria
I am between 50 and 100 years old.
My BMI is between 18 and 32, and I weigh less than 300 pounds.
My cognitive function is normal, as confirmed by a doctor.
I have been diagnosed with Alzheimer's disease, with mild to moderate symptoms confirmed by tests.
Exclusion Criteria
I have a genetic mutation linked to familial dementia.
I do not have a history of significant infectious diseases like AIDS or hepatitis.
I haven't lost or donated more than 450 mL of blood in the last 4 months, nor have I donated plasma in the last 14 days. I also don't have a bleeding disorder or take blood thinners.
I will be exposed to a high level of radiation due to tests and treatments.
I have not completed 2 COVID-19 vaccine shots.
Treatment Details
The study tests three new TAU radioligands (18F-MK6240, [18F]RO-948, 18F-GTP1) against the first-generation radioligand in imaging tauopathy in AD patients and healthy controls. Participants will receive up to three PET scans with these tracers to compare their effectiveness.
3Treatment groups
Experimental Treatment
Group I: Cohort 3: (A+; CDR = 0, .5, 1; AD)Experimental Treatment3 Interventions
Unblinded and randomized to receive 18F-RO948or 18F-MK6240 or \[18F\]GTP1for PET Scan #1. PET scan #2 will be 18F-RO948or 18F-MK6240 or \[18F\]GTP1NOT received in PET scan #1. PET scan # 3 will be 18F-RO948or 18F-MK6240 or \[18F\]GTP1NOT received in PET scan #1 or #2. Efforts will be made to include about 1/3 CDR = 0; 1/3 CDR = .5; 1/3 CDR = 1 in Cohort 3. Efforts will also be made to completethe study with about equal numbers of subjects whose PET scan #1 start with each of the three tracers.
Group II: Cohort 2: (A-; CDR=0; OC)Experimental Treatment3 Interventions
Unblinded and randomized to receive either 18F-RO948or 18F-MK6240 for PET Scan #1. PET scan #2 will be either 18F-RO948or 18F-MK6240 NOT received in PET scan#1.If a 3rdPET scan occurs, this third scan will always be \[18F\]GTP1.
Group III: Cohort 1: (A+; CDR = .5, 1; AD)Experimental Treatment3 Interventions
Unblinded and randomized to receive either 18F-RO948or 18F-MK6240 for PET Scan #1. PET scan #2 will be either 18F-RO948or 18F-MK6240 NOT received in PET scan #1. If a 3rdPET scanoccurs,this third scanwill always be \[18F\]GTP1.
Find a clinic near you
Research locations nearbySelect from list below to view details:
Washington University School of MedicineSaint Louis, MO
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Who is running the clinical trial?
Washington University School of MedicineLead Sponsor
Roche Pharma AGIndustry Sponsor
References
PET Radioligands for Imaging of Tau Pathology: Current Status. [2020]The incidence of Alzheimer's disease (AD), a progressive neurodegenerative disorder, continues to soar with the rapid growth of the elderly population, thus creating an enormous social and economic burden. Although disease-modifying drugs to treat AD are not yet available, several candidate drugs are in clinical trials. Most of these drugs are expected to be effective at the early stages of the disease, and therefore the early and accurate diagnosis of AD will be a critical factor in efforts to improve the prognosis of patients with AD. This review focuses on lead radioligands developed to date and their preclinical data in order to facilitate the development of tau-specific positron emission tomography radioligands that are of great interest to the scientific community.
Preclinical Evaluation of 18F-RO6958948, 11C-RO6931643, and 11C-RO6924963 as Novel PET Radiotracers for Imaging Tau Aggregates in Alzheimer Disease. [2022]Tau aggregates and amyloid-β (Aβ) plaques are key histopathologic features in Alzheimer disease (AD) and are considered targets for therapeutic intervention as well as biomarkers for diagnostic in vivo imaging agents. This article describes the preclinical in vitro and in vivo characterization of 3 novel compounds-RO6958948, RO6931643, and RO6924963-that bind specifically to tau aggregates and have the potential to become PET tracers for future human use. Methods: RO6958948, RO6931643, and RO6924963 were identified as high-affinity competitors at the 3H-T808 binding site on native tau aggregates in human late-stage AD brain tissue. Binding of tritiated compounds to brain tissue sections of AD patients and healthy controls was analyzed by macro- and microautoradiography and by costaining of tau aggregates and Aβ plaques on the same tissue section using specific antibodies. All 3 tracer candidates were radiolabeled with a PET nuclide and tested in vivo in tau-naïve baboons to assess brain uptake, distribution, clearance, and metabolism. Results:3H-RO6958948, 3H-RO6931643, and 3H-RO6924963 bound with high affinity and specificity to tau aggregates, clearly lacking affinity for concomitant Aβ plaques in human AD Braak V tissue sections. The specificity of all 3 radioligands for tau aggregates was supported, first, by binding patterns in AD sections comparable to the tau-specific radioligand 3H-T808; second, by very low nonspecific binding in brain tissue devoid of tau pathology, excluding significant radioligand binding to any other central nervous system target; and third, by macroscopic and microscopic colocalization and quantitative correlation of radioligand binding and tau antibody staining on the same tissue section. RO6958948, RO6931643, and RO6924963 were successfully radiolabeled with a PET nuclide at high specific activity, radiochemical purity, and yield. After intravenous administration of 18F-RO6958948, 11C-RO6931643, and 11C-RO6924963 to baboons, PET scans indicated good brain entry, rapid washout, and a favorable metabolism pattern. Conclusion:18F-RO6958948, 11C-RO6931643, and 11C-RO6924963 are promising PET tracers for visualization of tau aggregates in AD. Head-to-head comparison and validation of these tracer candidates in AD patients and healthy controls will be reported in due course.
An updated radiosynthesis of [18F]AV1451 for tau PET imaging. [2022]Label="BACKGROUND" NlmCategory="BACKGROUND">[18F]AV1451 is a commonly used radiotracer for imaging tau deposits in Alzheimer's disease (AD) and related non-AD tauopathies. Existing radiosyntheses of [18F]AV1451 require complex purifications to provide doses suitable for use in clinical imaging studies. To address this issue, we have modified the synthesis of [18F]AV1451 to use only 0.5 mg precursor, optimized the Boc-deprotection step and developed a simplified method for HPLC purification of the radiotracer.
Characterization of 3 Novel Tau Radiopharmaceuticals, 11C-RO-963, 11C-RO-643, and 18F-RO-948, in Healthy Controls and in Alzheimer Subjects. [2019]11C-RO-963, 11C-RO-643, and 18F-RO-948 (previously referred to as 11C-RO6924963, 11C-RO6931643, and 18F-RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data. Here we describe the first, to our knowledge, human evaluation of these novel radiotracers. Methods: Amyloid PET-positive Alzheimer disease (AD) subjects and younger controls each received 2 different tau tracers. Dynamic 90-min scans were obtained after bolus injection of 11C-RO-963, 11C-RO-643, or 18F-RO-948. Arterial blood sampling was performed on 11 healthy controls and 11 AD subjects. Regions were defined on MR images, and PET data were quantified by plasma reference graphical analysis (for total distribution volume) and target cerebellum ratio (SUV ratios of 60- to 90-min frames). SUV ratio images were also analyzed voxelwise. Five older controls each underwent 2 scans with 18F-RO-948 for evaluation of test-retest variability. Four AD subjects underwent a repeated 18F-RO-948 scan 6-22 mo after the first scan. Six additional healthy controls (3 men and 3 women; age range, 41-67 y) each underwent 1 whole-body dosimetry scan with 18F-RO-948. Results: In younger controls, SUVpeak was observed in the temporal lobe with values of approximately 3.0 for 11C-RO-963, 1.5 for 11C-RO-643, and 3.5 for 18F-RO-948. Over all brain regions and subjects, the trend was for 18F-RO-948 to have the highest SUVpeak, followed by 11C-RO-963 and then 11C-RO-643. Regional analysis of SUV ratio and total distribution volume for 11C-RO-643 and 18F-RO-948 clearly discriminated the AD group from the healthy control groups. Compartmental modeling confirmed that 11C-RO-643 had lower brain entry than either 11C-RO-963 or 18F-RO-948 and that 18F-RO-948 showed better contrast between (predicted) areas of high versus low tau accumulation. Thus, our subsequent analysis focused on 18F-RO-948. Both voxelwise and region-based analysis of 18F-RO-948 binding in healthy controls versus AD subjects revealed multiple areas where AD subjects significantly differed from healthy controls. Of 22 high-binding regions, 13 showed a significant group difference (after ANOVA, F(1,21) = 45, P < 10-5). Voxelwise analysis also revealed a set of symmetric clusters where AD subjects had higher binding than healthy controls (threshold of P < 0.001, cluster size > 50). Conclusion:18F-RO-948 demonstrates characteristics superior to 11C-RO-643 and 11C-RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of 18F-RO-948 compare favorably with other existing tau PET tracers.
Evaluation of 18F-RO-948 PET for Quantitative Assessment of Tau Accumulation in the Human Brain. [2019]The availability of tau PET radioligands enables quantitative assessment of tau density and distribution in the human brain. We evaluated the kinetics of a novel radioligand, 18F-RO-948 (previously referred to as 18F-RO6958948), and its ability to identify tau positivity in individual patients with mild Alzheimer disease (AD). Methods: Eleven subjects with amyloid-positive mild AD, 5 amyloid-negative older control subjects (OC), and 5 younger control subjects (YC) completed 1 or 2 (4 AD and 5 OC) PET scans with 18F-RO-948 for 90, 120, or 200 min. The kinetics of the radioligand was evaluated with standard compartmental and noncompartmental models (with plasma data in 70% of cases), tissue-reference methods, and SUV ratio. These approaches were applied to assess the ability of 18F-RO-948 to discriminate AD subjects from OC subjects. Results: The plasma reference graphical analysis appeared to be the optimal method of quantification for 18F-RO-948, yielding strictly time-consistent values of distribution volume and distribution volume ratio at 90 min against the analyses at 120 and 200 min. The reference tissue graphical analysis and SUV ratio were cross-validated against plasma reference graphical analysis. Test-retest evaluation showed excellent reproducibility. A proposed novel index of tau load, the regional tau-positive fraction, showed high values in the medial and lateral temporal and parietal regions in AD and successfully separated AD subjects from OC and YC subjects with a significant margin. Conclusion:18F-RO-948 appears to be a promising radioligand for quantitative imaging of tau in the brain of AD patients.
Preclinical Safety Evaluation and Human Dosimetry of [18F]MK-6240, a Novel PET Tracer for Imaging Neurofibrillary Tangles. [2021]Label="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.
Evaluation of pharmacokinetic modeling strategies for in-vivo quantification of tau with the radiotracer [18F]MK6240 in human subjects. [2023]Label="PURPOSE" NlmCategory="OBJECTIVE">[18F]MK6240 was developed for PET imaging of tau aggregates, which are implicated in Alzheimer's disease. The goal of this work was to evaluate the kinetics of [18F]MK6240 and to investigate different strategies for in-vivo quantification of tau aggregates in humans.
Characterization of MK6240, a tau PET tracer, in autopsy brain tissue from Alzheimer's disease cases. [2021]Label="PURPOSE">MK6240 is a second-generation tau PET tracer designed to detect the neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). The aim of the study was to characterize 3H-MK6240 in AD and control brain tissue and to compare its binding properties with those of first-generation tau PET tracers.