Quantification of Hsp90 in the Human Brain
Trial statusRecruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age18-70
SponsorUniversitaire Ziekenhuizen KU Leuven
About this trial
This study tests the radiolabeled molecule ("tracer"), \[¹¹C\]HSP990, using positron emission tomography (PET) imaging to assess whether it can be used to measure levels of Heat Shock Protein 90 (Hsp90). The protein Hsp90 plays an important role in how proteins in the brain fold into their three-dimensional structure and how this protein helps maintain cellular homeostasis. Since neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by disrupted three-dimensional protein folding resulting in protein aggregation, we also aim to measure Hsp90 levels in patients with these conditions.
\[¹¹C\]HSP990 is a promising tracer for this purpose and has already been extensively tested in animal models with safe and favorable results. The investigator now aims to evaluate this tracer in the human brain in healthy volunteers as well as in patients with Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. The investigator expects that Hsp90 protein levels will be present at reduced concentrations in patients, possibly in different brain regions depending on the distribution of the disease-causing proteins associated with these disorders.
Since the discovery of the important role of Hsp90 in neurodegenerative diseases, several candidate drugs targeting Hsp90 have been developed in recent years. The imaging method used in this study may support the development of Hsp90-targeting medications by enabling measurement of Hsp90 levels in the brain and assessment of the effects of these drugs.
Eligibility criteria
This trial accepts healthy volunteersQualifiers
Voluntary written informed consent of the participant or their legally authorized representative has been obtained prior to any screening procedures
Use of highly effective methods of birth control; defined as those that, alone or in combination, result in low failure rate (i.e., less than 1% per year) when used consistently and correctly; such as implants, injectables, combined oral contraceptives, some IUDs, true sexual abstinence (i.e. refraining from heterosexual intercourse during the entire period of risk associated with the Trial treatment(s)) or commitment to a vasectomised partner.
Male or female subjects, age between 18-55 (Part 1, n = 3), 18-40 (Part II, n = 5) or 40-70 (Part III, 40-55 n = 5, 55-70 n = 5) years old.
Subject is judged to be in good health by the investigator on the basis of medical history, physical examination including vital signs, clinical laboratory test and urinalysis.
Disqualifiers
Participant has a history of any major disease that may interfere with the investigations or make the subject unfit for participation according to the interpretation by the investigator (especially diabetes mellitus, heart disease, liver and kidney disease, or most forms of cancer).
Any prior or concomitant treatment(s) that might jeopardise the participant's safety or that would compromise the integrity of the Trial .
Participation in an interventional Trial with an investigational medicinal product (IMP) or device.
Evidence of cognitive impairment.
Trial design
Design model
Sequential
Treatments tested in this trial
[11C]HSP990 PET dosimetry
Other intervention120 minute whole body PET/CT scan with \[11C\]HSP990 radiotracer
[11C]HSP990 PET test-retest
Other intervention2 120-minute brain PET scan with \[11C\]HSP990 radiotracer
[11C]HSP990 simplified scan protocol
Other interventionSimplified quantitative \[11C\]HSP990 PET scan as will be determined in part 2.
Treatment groups
48 Participants
are divided into 3 treatment groupsGroup A: 1: Biodistribution and dosimetryExperimental treatment 1 intervention
Group B: 2: Kinetics and variability in the brainExperimental treatment 1 intervention
Group C: 3: Comparison with patient groupExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
Quantification of HSP90 in the human brain
To quantify and compare Hsp90 levels in vivo in the human brain of healthy volunteers and patients with neurodegenerative disorders using the novel PET radioligand \[11C\]HSP990.
Time frame
This will be assessed right after each scan in cohort 2 and 3. (Estimated visit lenght in cohort 2 will be 4 hours for each scanning procedure. In cohort 3 this will be optimized based on the results of cohort 2.)Secondary outcomes
1
To assess the safety and clinical tolerance of [11C]HSP990 administration.
The impact of \[11C\]HSP990 administration on clinical symptoms and signs and biochemistry values will be evaluated. Baseline values will be recorded and subjects will be assessed clinically and with dual biochemical analysis (before PET and after PET). Adverse events will be scored as mild, moderate or severe. We hypothise that administration of \[11C\]HSP990 is safe and in view of the low mass dose (\< 10 µg) does not result in significant changes in vitals, clinical assessment or biochemistry, or subjective complaints other than those that may be related to the procedure (e.g., catheter placement).
Time frame
From enrollment until 1 week after completion of scan.2
To determine the radiation dosimetry of [11C]HSP990 in humans.
Effective doses will be determined. The hypothesis is that in young healthy volunteers administration of \[11C\]HSP990 results in significant brain uptake and is partially hepatobiliary and renally cleared, and results in an effective dose between 3 to 8 microSv/MBq.
Time frame
This will be assessed right after each scan in cohort 1. (Estimated lenght of the scanning visit is 4 hours.)3
To determine the optimal brain tracer kinetic modelling approach and test-retest variation (TRV) for [11C]HSP990 brain PET in humans.
Total distribution volume (VT) for \[11C\]HSP990 will be determined using the arterial brain input and response function. The hypothesis is that \[11C\]HSP990 PET allows for quantifying total Hsp90 distribution volume in the human brain with a 2TCM as the preferred quantitative approach. VT for \[11C\]HSP990 re-test scans will be determined and TRV will be calculated. The hypothesis is that the absolute short term test-retest will be acceptable (below 10 %).
Time frame
This will be assessed right after each scan in cohort 2. (Estimated lenght of each scanning visit is 4 hours.)4
To determine the optimal imaging protocol for quantifying Hsp90 levels in human brain using [11C]HSP990 and develop if possible, a simplified imaging protocol or patient comfort.
It will be assessed if less invasive shorter imaging protocols can lead to equivalent outcome parameters in terms of VT. The hypothesis is that dynamic \[11C\]HSP990 PET combined with an image-derived input function and venous blood sampling based radiometabolite quantification can be used as a less invasive imaging protocol to quantify Hsp90 levels in human brain. Moreover, a shorter simplified coffeebreak protocol (e.g. 0-50 min p.i. dynamic imaging followed by 20 min break and 20 min dynamic imaging) can be used as a more patient friendly and shorter imaging protocol.
Time frame
This will be assessed right after each scan in cohort 2. (Estimated lenght of the scanning visit is 4 hours.)Sponsors and contacts
Click on the lead sponsor to view all of their trials.
Source ClinicalTrials.gov