[18F]MC225-PET: Assessment of the blood-brain barrier integrity and P-glycoprotein function in healthy volunteers,a pilot study

Accumulation of neurotoxic amyloid (Aβ) in the brain is a pathological hallmark
of Alzheimer*s disease (AD). Development of new treatment strategies aims to
reduce Aβ load in the brain. Transporters at the blood-brain barrier (BBB) are
involved in the efflux of neurotoxic substances, and more specifically the
transport pump P-glycoprotein (P-gp) has been shown to be involved in Aβ
efflux. Up until now [11C]verapamil is considered to be the gold standard to
measure P-gp function and it showed decreased P-gp function in AD patients.
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 new
developed PET tracer to measure P-gp function, [18F]-MC225, has the potential
advantage of higher brain uptake values at baseline and is therefore able to
measure both up- and down regulation P-gp function, which is important in
measuring the effect of p-gp inducers in future research studies.

Translation of [18F]-MC22518 to the clinic to measure P-gp function in healthy
volunteers.

Intervention study in which ten healthy volunteers aged 50-80 will undergo two
dynamic [18F]-MC225-PET scans with arterial plasma sampling. Prior to the scan
a H2O PET scan will be performed to estimate the cerebral perfusion rate. A MRI
with gadolinium contrast as anatomical reference and BBB integrity assessment
will be performed. Five of these healthy volunteers will undergo the second
dynamic PET scan after administration of Cyclosporin to reach a blocked P-gp
state. The remaining five volunteers will undergo a second [18F]MC225 in
test-retest setting, in order to correct the validation of [18F]MC225 for
variability.

1. Administration of radiopharmacon [18F]MC225
2. Arterial and venous plasma sampling
3. Administration of one gift Cyclosporin (registered pharmaceutical) to cause
inhibition of p-gp function in five volunteers

This study will include healthy adult volunteers. Ten subjects will undergo two
dynamic PET scans in three visits to the department of nuclear medicine and
molecular imaging. The visits will take approximately 3-4 hours. During this
visit a blood sample will be obtained to measure the renal function (eGFR),
since an impaired renal function is a contra-indication for Cyclosporin and
gadolinium contrast. Also, a neurological examination will be performed and a
mini mental state examination will be scored. Before the PET scans a radial
arterial line will be placed by an anaesthesiologist for blood sampling at
several predetermined time intervals during the PET scans. [18F]-MC225 will be
administered through a line placed intravenously in the elbow. Since for PET
tracer studies microdoses of the investigational products are used, no
toxicological effects are expected (microdoses are far below the toxicological
value of 1.5 µg a day). The subjectis will be exposed at a radiation dose of a
maximum of 6.6 mSv in total (minor-intermediate risk classification according
to the International Commission on Radiological Protection (ICRP). During the
second visit, the healthy subjects will also undergo a gadolinium
contrast-enhanced MRI, which is used as anatomical reference and for
measurement of blood-brain barrier integrity with MRI-VAI sequence. Five out of
these ten subjects will undergo a second [18F]MC225-PET scan after inhibition
of the p-gp function using Cyclosporin to validate the tracer specificity.
Since cyclosporin is a registered pharmaceutical with extensive use in clinical
practice and side effects of cyclosporin normally only occur in longterm use in
high dosages there are no harmful effects expected of the administration of one
gift CyclosporinThe remaining five subjects will undergo a second [18F]MC225
PET scan without Cyclosporin, in a test-retest setting.