[11C]MeDAS PET: an imaging tool for quantitative assessment of changes in myelin density over time in multiple sclerosis

Multiple sclerosis (MS) is a neurodegenerative disease, in which myelin sheaths
in the brain and spinal cord are damaged. If repair of myelin damage is
incomplete, nerve terminals will be irreversibly destroyed, leading to
neurological symptoms. Ineffective remyelination is probably a major underlying
mechanism resulting in irreversible neurological impairments in the progressive
phase of MS. Most therapies aim to stop inflammatory processes associated with
the myelin damage, but all lack efficacy in progressive MS so far. Strategies
that promote myelin repair are promising, but still under investigation.
Non-invasive imaging of myelin damage and repair could enable better disease
characterization and accelerate evaluation of new interventions. Although MRI
is successfully used in MS diagnosis, it cannot quantify myelin changes. We
have demonstrated in animal models for MS that damage and repair of myelin can
be visualized and quantitatively measured by PET using the newly developed
tracer [11C]MeDAS. In addition, our previous study showed the feasibility to
image differences in myelin density using this tracer in human subjects. During
the first in human [11C]MeDAS scans, no adverse events occurred and both the
scan protocol as well as the scan itself were well tolerated. Preliminary
results indicate that [11C]MeDAS binds primarily to white matter and is rapidly
metabolised, which leads to a fast clearance from the body. The data suggests
that [11C]MeDAS might have the potential to determine the efficacy of
remyelination therapies, which has to be confirmed by performing scans in a
longitudinal fashion. We now aim to investigate the applicability of [11C]MeDAS
to image changes in myelin density over time and thereby determine the efficacy
of [11C]MeDAS PET to image myelin degradation and repair. The scanning
procedure will be performed in patients with progressive MS and results will be
correlated to MRI results and (changes in) clinical symptoms. In progressive
MS, myelin loss is expected to outweigh spontaneous remyelination.

The objective of this study is to evaluate [11C]MeDAS PET as a quantitative
method for assessment of changes in myelin density over time and thus the
efficacy of [11C]MeDAS PET to image myelin degradation and repair.

The design of this study is a diagnostic intervention, validating [11C]MeDAS as
a myelin tracer in MS patients for imaging changes in myelin density over time.

The subjects will undergo two PET scans (with an interval of 9-12 months) with
the myelin tracer [11C]MeDAS, which binds to β-sheet structures within intact
Myelin Basic Protein (MBP). In addition, the subjects will undergo two MRI
scans for comparison.

The subjects in this study will undergo two [11C]MeDAS PET scans with
approximately 1 year interval. During the PET scans, 260 ml of blood is taken
for radioactivity and radiometabolites measurements. At both time points, a MRI
scans will also be made. For the PET scans, the subjects have to come to the
UMCG two times. The MRI scans will be combined with these visits. The adverse
events can be a bruise as a result of the arterial catheter or an idiosyncratic
reaction to the tracer. The injected mass of [11C]MeDAS is negligible and
idiosyncratic reactions are rare to occur for radioactive PET tracers.
Nevertheless, a physician will be available during each injection of the
tracer. In addition, the radiation burden the subjects in this study are
exposed to of 3.6 mSv, is within category IIb (1-10 mSv, minor to moderate
risk), according to the International Commission on Radiological Protection
(ICRP62). The subjects will not directly benefit from the study, but will help
to evaluate the reliability of a measurement for myelin quantification. Such a
method can aid the development of treatments that promote remyelination, by
being able to directly quantify myelin density. For the MRI protocol,
gadolinium is used, which can cause adverse events in 0.4% of cases. These
adverse events are feeling warmth, brief headache or dizziness, all these
events are reversible and disappear immediately after injection. During the
first in human [11C]MeDAS scans, no adverse events occurred and both the scan
protocol as the scan itself were well tolerated. Preliminary results indicate
that [11C]MeDAS binds primarily to white matter and is rapidly metabolised,
which leads to a fast clearance from the body. The data suggests that
[11C]MeDAS might have the potential to determine the efficacy of remyelination
therapies, which has to be confirmed by performing scans in a longitudinal
fashion.