Evaluation of [18F]MC225 to measure P-glycoprotein function in neurodegenerative disease

A decrease in P-glycoprotein (P-gp) function is associated with the onset of
neurodegenerative disease (1,2). Development of new treatment strategies aim to
restore the P-gp function. To measure effect of such therapies, measurement of
the P-gp function is necessary. Up until now [11C]verapamil is considered to be
the gold standard to measure P-gp function(3,4). However tracer uptake in the
brain of [11C]verapamil is too low for adequate measurement of treatment
effect, especially of restoring P-gp function. A novel PET tracer to measure
P-gp function, [18F]MC225, has the potential advantage of higher brain uptake
values at baseline and might therefore able to measure both up- and down
regulation P-gp function. (5,6). [18F]MC225 was studied recently in healthy
volunteers and showed promising results and a solid method to quantify P-gp
function was developed (7). Since the study in healthy volunteers showed
promising results, we would like to continue our research of [18F]MC225 under
pathological conditions in neurodegenerative disease.

This study has been transitioned to CTIS with ID 2024-518865-85-00 check the CTIS register for the current data.

Primary objective
Evaluation of [18F]MC225 to measure the P-glycoprotein function in Alzheimer*s
disease, Mild Cognitive Impairment and Parkinson*s disease.

Secondary objectives
1. Evaluation of blood-brain barrier integrity using [18F]MC225 and MRI VAI
sequence in Alzheimer*s disease, MCI and Parkinson*s disease.
2. Evaluation of perfusion measurements using both [15O]H2O PET and MRI (DSC,
DCE) to simplify the scan protocol in further [18F]MC225 studies.

60 minute [18F]MC225 PET scans will be performed in 10 Alzheimer patients, 10
MCI patients and 10 Parkinson patients. Prior to the [18F]MC225 PET scan a 10
min dynamic [15O]H2O PET will be performed to measure the effect of cerebral
blood flow on the uptake of [18F]MC225 in the brain. For both scansthe PET
scans arterial blood sampling is needed to enable kinetic modeling of the
[18f]MC225 PET tracer. In addition to the PET scans, every subject will undergo
an MRI scan as anatomical reference to the PET scan. One week before the scans
a neurological examination (assessment of sensory neuron and motor responses
and reflexes) and a mini mental state examination (MMSE) will be performed by a
physician. [18F]MC225 brain uptake in the patient groups will be compared with
the brain uptake of healthy volunteers obtained in our previous study.
For this study a duration of two years one year and six months is expected.

Participants will not have any direct benefit from the study, but this study
will help to evaluate the reliability of [18F]MC225 as a measurement for P-gp
function. Such a method aids the development of P-gp inducers, by being able to
quantify increases in the function of P-gp.
[18F]MC225: A standard dose of 200 MBq [18F]MC225 with a molar activity
> 25.000 GBq/mmol results in an injected mass > 4 µg. Since the total dose
administered as a single dose or divided doses in any subject will be far less
than 100 µg and is estimated to be <1/100th of the NOAEL and pharmalogically
active dose, PET studies with [18F]MC225 can be considered as microdosing
studies conform the European Medicines Agency IHC guideline M3(R2) on
non-clinical safety studies for the conduct of human clinical trials and
marketing authorisation for pharmaceuticals, Chapter 7 (EMA/CPMP/ICH/286/1995).
The injected mass of [18F]MC225 is negligible and idiosyncratic reactions are
rare to occur for radio PET tracers. Nevertheless, a physician will be
available during each injection of the tracer.
Preclinically, both acute toxicity as the Ames test and the cardiovascular
safety evaluation were performed to study toxicity of [18F]MC225. Both tests
concluded no acute toxicity and mutagenicity of MC225 or [18F]MC225 injection
were observed. The methodology and the results of the complete toxicity tests
are included in the IMPD, chapter Toxicology. In a recent study of [18f]MC225
in healthy volunteers no side effects were reported.
Dotarem - Dotarem is a gadolinium MRI contrast agent which is used in
clinical routine. Adverse events occur in about 0.4% of cases, these events are
feeling warmth, brief headache or dizziness. All these events are reversible
and disappear immediately after injection.
Adverse effects - Adverse events in this study can be a bruise as a
result of the arterial catheter or an allergic reaction to the PET-tracer or
gadolinium.

f. Pharmacokinetic considerations
The use of radioactive isotopes in PET imaging implies exposure of patients or
healthy volunteers to radiation. The estimated radiation-absorbed doses were
calculated by a radiation expert and the total effective dose is 3.3 mSv, which
is below the effective annual radiation dose limit of 20 mSv/y. The radiation
dosimetry of [18F]MC225 is comparable to that of other regularly used PET
tracers. According to international commission of radiological protection
(ICRP) Publication 62, the radiation burden of [18F]MC225 belongs to risk
category IIb (1-10 mSv, minor to intermediate risk). It can be concluded that
[18F]MC225 has a favorable radiation dose profile in humans, allowing multiple
PET examinations per year to be performed on the same subject.