Biperiden pharmacological-MRI as a tool to assess the function of the central cholinergic system: a validation study

At present brain neurotransmission is typically visualized using positron
emission tomography (PET) and single photon emission computed tomography
(SPECT), techniques that involve radiopharmaceuticals. However, a recently
developed technique called, pharmacological Magnetic Resonance Imaging (phMRI),
allows measuring effects of pharmaceuticalspharmaca on the brain in a
non-radioactive manner. Because with MRS it is possible to measure metabolite
changes induced by a pharmacological challenge, radioactive compounds are not
necessary. This novel approach yields a lot of information on how
pharmaceuticals moderate brain function and how this response is altered in
patients with a psychiatric disorder such as major depression, attention-
deficit hyperactivity disorder (ADHD) or neurodegenerative disorders as
Alzheimer*s or Parkinson*s disease.

We aim to validate MRS with a cholinergic challenge as method to investigate
muscarinic M1 receptor functioning. To investigate the relationship between the
response to a muscarinic receptor antagonist with biperiden phMRI and
[123I]IDEX SPECT imaging.

The study is a cross-sectional single blind placebo-controlled study. All
participants will receive SPECT imaging using [123I]IDEX on one occasion to
assess brain M1 receptor availability. Participants will then undergo two MRS
scanning sessions to measure concentrations of free choline: once under a
cholinergic challenge with biperiden, and once after receiving a placebo.

MRS is a non-invasive imaging tool, which can also be used to measure
drug-induced responses. Mild reversible unwanted effects have been found at 4
mg of biperiden administration (i.e. dry mouth, obstipation, concentration
difficulties) but these are transient if occur. The radiation exposure of the
SPECT scan is classified as category IIb (intermediate), and frequently
conducted at the department of nuclear medicine AMC both in patients and in
healthy human volunteers. Moreover, [123I]IDEX will be produced according to
GMP criteria quality benchmark. Therefore, the risk involved in participating
in this study should be considered negligible. The nature of the burden is
classified as moderate considering that subjects will have to come to the AMC
on 2 separate occasions and undergo 2 different types of scans. For the SPECT
scan the nature of the burden is 1 venous puncture and for the MRI scan
participants will be given biperiden orally as cholinergic challenge. No
serious side effects of biperiden are foreseen