[11C]MeDAS PET: a non-invasive imaging tool for quantitative assessment of myelin loss in multiple sclerosis

Multiple sclerosis (MS) is a 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 recently
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. We now aim to make [11C]MeDAS PET available for clinical
investigations of myelin density in the brain and spinal cord. The scanning
procedure will be validated in patients with progressive MS and correlated to
MRI results and (changes in) clinical symptoms.

We and others have clearly demonstrated in animal models of MS that the
[11C]MeDAS PET signal correlates well with myelin density and therefore can be
used to monitor myelin loss and repair in vivo. These promising preclinical
results warrant translation to application in humans. The objective of this
project is to evaluate [11C]MeDAS PET as a quantitative method for assessment
of myelin density and to develop the optimal scanning protocol for application
in humans.

This study will evaluate [11C]MeDAS PET in patients with Multiple Sclerosis and
assess the analysis methods to obtain reliable quantitative PET measures. Based
on clinical history and available MRI scans, 5 SPMS patients and 5 PPMS
patients will be included. All will receive a [11C]MeDAS PET scan at baseline
and another [11C]MeDAS PET scan one week later, in order to investigate the
test-retest variability in the measures of myelin density. Information on
test-retest variability is especially important when longitudinal changes or
response to therapy is measured. For the first PET scan, a venous catheter and
a wrist arterial cannula will be placed. Approximately 400 MBq of [11C]MeDAS
will be injected during 1 minute intravenously (IV) followed by a flush.
Immediately following injection, a dynamic 70 minute PET scan will be
performed. Arterial blood will be withdrawn continuously from 0-60 minutes
using an online detection system which will be cross-calibrated against the PET
scanner. At set times, additional manual blood samples will be taken to measure
whole blood and plasma radioactivity concentrations. In addition, plasma
samples will be used to determine the fraction of radioactivity that
corresponds to intact [11C]MeDAS. No more than 175cc of blood will be withdrawn
during the PET session. After the first PET scan, a MRI scan is performed. The
sequences used are T1 with gadolinium contrast, T2 and FLAIR, which are
standard sequences for multiple sclerosis, furthermore myelin MRI and perfusion
MRI is performed using the same gadolinium contrast (0.2 mmol/kg Dotarem) as
for the acquisition of the T1 sequence. The perfusion MRI scan is performed to
discriminate whether differences in PET tracer uptake are caused by
microvascular damage (decreased tracer delivery) or a decrease in myelin
density. Approximately one week following the baseline scan, subjects will
return to the clinic for a second [11C]MeDAS PET scan. Subjects will undergo
the same safety procedures as the baseline PET visit except for arterial
catheter placement, arterial blood sampling and MRI scan. If there are any
hitherto unknown clinically relevant abnormalities these will be communicated
to the subjects* general practitioner in line with METc/IRB guidelines.
Following each [11C]MeDAS PET visit, a follow-up phone call to the subject will
be conducted 2 or 3 business days after the imaging day, but not before 48
hours post-injection, to confirm the subject*s well-being and to collect
information about any new adverse events. If both of these days are not
business days, the follow-up phone call can occur the following business day.

There will be two [11C]MeDAS PET scans performed to assess the feasibility and
test-retest variability of this myelin imaging method. The first [11C]MeDAS PET
scan will be performed with arterial blood sampling and the second [11C]MeDAS
PET scan will be done without. In addition, a MRI scan will be performed for
co-registration of the PET images and for obtaining anatomical information to
determine regional tracer uptake.

At present, there is no adequate method to quantify myelin loss and restoration
in lesions of MS patients. Absence of such a method hampers the development of
treatments that aim to restore myelin damage in MS patients. [11C]MeDAS PET
will be validated as a imaging method to quantitatively assess myelin density
in MS patients. Clinical validation of [11C]MeDAS PET is an important step to
move research on innovative treatments that stimulate myelination in MS lesions
forward. Moreover, the method could enable better patient characterization,
stratification and evaluation of treatment strategies.
[11C]MeDAS is a myelin radioligand which provide most promising results as a
myelin tracer in animal studies. However, no clinical data are available for
this tracer yet. The LD50 of [11C]MeDAS in mice was determined to be 141
mg/kg. For a PET scan in humans, a typical dose of 400 MBq [11C]MeDAS is
injected, which corresponds to a mass of less than 4 µg of the tracer. This
microdose of the PET tracer is 6 orders of magnitude lower than the LD50 in
mice. Therefore no toxicological effects are expected for a tracer dose of
[11C]MeDAS.
In mice, highest tracer uptake was observed in liver, lung, brain, GI tract and
adrenals. After administration of [11C]MeDAS in mice, almost all activity in
the organs consisted of the intact tracer. The radioactive metabolites of
[11C]MeDAS in plasma, were all more hydrophilic than the intact tracer,
suggesting that metabolites are less likely to cross the blood-brain barrier.
No adverse effects were observed when a tracer dose of [11C]MeDAS was injected
in mice or rats.
The estimated effective dose in humans based on the finding in mice is 2.99µSv/
MBq, which is comparable to other 11C-labeled PET tracers. For an injected dose
of 400 MBq [11C]MeDAS, the effective dose corresponds to a radiation burden to
the patient of 1.2 mSv, 1.8 mSV per scan and 3.6 mSv for the complete study,
which is within category IIb (1-10 mSv; minor to moderate risk), as defined by
the International Commission on Radiological Protection (ICRP).