OSU6162 as a potential novel drug treatment for Parkinson's disease: effects on dopamine D2 receptor binding in human brain studied using PET.

Rationale: Chronic levodopa therapy in Parkinson*s disease (PD) is associated
with the development of disabling dyskinesias (involuntary movements with a
choreic or dystonic character). After five years of levodopa treatment
approximately 30% of patients will suffer from dyskinesias, increasing to 60%
after 10 years of treatment (1). The development of anti-dyskinetic agents is
therefore an important challenge. An interesting class of drugs are the
so-called dopamine stabilizers, which cause dopaminergic inhibition in a state
of elevated dopamine function, and enhance dopaminergic signalling under
conditions of low dopaminergic tone (2). Conceivably, such drugs might reduce
dyskinesias in PD by inhibiting dopaminergic signalling while at the same time
avoiding increasing parkinsonism associated with low dopamine levels.
(-)-OSU6162 is one of these compounds. Preliminary case studies in advanced PD
patients using single dose intravenous infusion of (-)-OSU6162 have shown a
reduction in levodopa-induced dyskinesias up to 3* hours after infusion.
Studies in animal models of PD, including the MPTP-treated monkey, have shown
that (-)-OSU6162 antagonizes both the expression and the development of
levodopa-induced dyskinesias. The mechanism of action of (-)-OSU6162 remains to
be fully elucidated. Preclinical studies are indicative of positive allosteric
modulatory effects on dopamine D2L receptors, and orthosteric antagonistic
effects on D2L and D2S receptors. In the monkey, administration of (-)-OSU6162
reduced striatal binding of the selective D2-antagonist [11C]raclopride by an
unexpectedly high level of 76% (3), which might indicate that the binding of
dopamine to its receptor can indeed be made tighter with (-)-OSU6162. The
D2-ligand displacing potential of (-)-OSU6162, as an indication for a positive
allosteric modulatory effect of (-)-OSU6162, has never been studied in the
human brain.

To replicate the dose-dependent D2-ligand displacing action of (-)-OSU6162 in
the human brain and to determine the optimal dose of (-)-OSU6162 required to
achieve a significant amount of D2-ligand displacement in humans.

[11C]raclopride PET scanning will be performed twice on the same day in twelve
male healthy volunteers, aged 50-60 years, before and after the administration
of a single oral dose of (-)-OSU6162. Initially, the effect of 30 mg of
(-)-OSU6162 will be determined in two individuals. After this first dosing of
30 mg, the data will be analyzed and the effect and possible side effects will
be discussed in the team to decide on the next dosage. The dosing schedule is
adaptable according to findings with the previous dose, including a reduction
in dose. Steps in dose escalation will be of 15 mg up to a dose of 60 mg with a
final increase in dose of 30 mg up to a dose of 90 mg in a single step. For the
dose with optimal displacement of [11C]raclopride, the group will be expanded
to six individuals. The time interval between the two [11C] raclopride PET
scans will be four hours. The second scan will be performed one hour after the
single oral dose of (-)-OSU6162.

Venous sampling
There is a very small risk of infection and bleeding associated with
intravenous catheters, which is prevented by proper techniques.

Radiation exposure
The effective dose equivalent (EDE) of 1 PET study with [11C]raclopride is 2,5
mSv. For comparison, the natural background radiation dose in the Netherlands
gives an annual dose of 2 - 2.5 mSv. Thus, the total radiation exposure of one
PET study with [11C]raclopride is within an acceptable range. In case of
previous exposure to radioactivity, subjects will be eligible if the yearly
cumulative dose due to exposure to radiation remains below 10 mSv.

Administration of (-)-OSU 6162
Preclinical safety and toxicology studies have been performed by Pfizer
(formerly Upjohn/Pharmacia); IND was submitted to FDA by Pharmacia. Swedish
drug administration authorities (Läkemedelsverket) allowed clinical studies up
to 28 days duration. Safety data for (-)-OSU6162 are available from a British
phase I study using single oral doses up to 200 mg (7). Potential adverse
effects of (-)-OSU6162 administration are on the central nervous system and the
cardiovascular system. Single oral doses of (-)-OSU6162 up to 150 mg are well
tolerated; side effects are mild to moderate and involve dizziness, headache,
nausea, paresthesias, taste perversion, and somnolence. Safety monitoring will
include ECG, heart rate, blood pressure and QTc interval measurements. The
maximum dosage of (-)-OSU 6162 in the proposed study will be 90 mg oral.