Een onderzoek naar de veiligheid en farmacologie van een enkelvoudige dosering LY2165766 waarbij LY2165766 voor het eerst aan de mens wordt toegediend waarbij ook de bezetting van dopamine D2 receptor in de hersenen wordt onderzocht door positron emissie tomografie (PET)

Schizophrenia is a serious chronic psychiatric disease that is characterized by
auditory hallucinations and delusions (*positive symptoms*), and deficits
(*negative symptoms*) including an inability to pay attention, loss of a sense
of pleasure, loss of will or drive, disorganization or impoverishment of
thought and speech, flattening of affect, social withdrawal, and cognitive
dysfunction as manifested by a decreased ability to focus attention and
deficiencies in short-term verbal and nonverbal memory. Patients are at risk
for committing violent acts in response to hallucinations or delusions. The
current pharmacologic therapy of schizophrenia is centered on drugs that cause
dopamine D2 receptor blockade. The first-generation antipsychotic drugs such as
haloperiodol were shown to block D2 receptors and demonstrated therapeutic
efficacy. However, these drugs were associated with significant adverse
effects. A second generation of D2 blocking antipsychotics are now the
preferred agents to treat schizophrenia, and these agents are less tightly
bound to the D2 receptor. The first of these second generation antipsychotics
known as *atypical antipsychotics* was associated with a decrease in the side
effects associated with the first generation antipsychotics, but has been
associated with agranulocytosis which initially caused a number of fatalities,
but is now managed by frequent monitoring of blood cell counts. Newer atypical
antipsychotics are now available, but these are, however, not devoid of adverse
effects, including some adverse effects associated with the earlier drugs.
These events include sedation, moderate degrees of EPS, hypotension, weight
gain, hyperlipidemia and its consequences, and hyperprolactinemia, each of
which occur at different frequencies for any given individual atypical
antipsychotic. An atypical antipsychotic with appropriate D2 blocking
properties and with no or a low incidence of the these adverse effects is a
potentially attractive therapeutic agent.

Part A
Primary:
to evaluate the safety and tolerability of LY2165766 administered as a single
oral dose in healthy volunteers

Secondary:
to determine the pharmacokinetics of LY2165766

Part B
Primary:
to explore the relationship between plasma concentration and brain dopamine D2
receptor occupancy (D2RO) after a single dose of LY2165766 in healthy subjects

Part C
Primary:
to explore the relationship between plasma concentration and brain dopamine D2
receptor occupancy (D2RO) after a multiple dose of LY2165766 in healthy subjects


Secondary:
to characterize the brain dopamine D2 receptor occupancy (D2RO) relationship to
LY2165766 dose and to further evaluate the safety and tolerability of LY2165766
after single dose

A single-site, double-blind, placebo-controlled, alternating panel, single-dose
escalation study with two cohorts of nine healthy male subjects each receiving
a single oral dose of LY2165766 or placebo (six verum and three placebo) on
three occasions; treatment periods for each cohort will be separated by a
washout of at least seven days.

A multiple dose, open study with one cohort of 3 healthy male subjects each
receiving a multiple dose of LY2165766 once daily on days 1 - 7.

Part A Cohort 1 period 1: a single oral dose of 2 mg LY2165766 or placebo on Day 1 in the fasted state period 2: a single oral dose of 10 mg LY2165766 or placebo on Day 1 in the fasted state period 3: a single oral dose of 50 mg LY2165766 or placebo on Day 1 in the fasted state Cohort 2 period 1: a single oral dose of 4 mg LY2165766 or placebo on Day 1 in the fasted state period 2: a single oral dose of 25 mg LY2165766 or placebo on Day 1 in the fasted state period 3: a single oral dose of 100 mg LY2165766 or placebo on Day 1 in the fasted state Part B Cohort 1: a single oral dose of 4 mg LY2165766 on Day 1 in the fasted state Cohort 2: a single oral dose of 6 mg LY2165766 on Day 1 in the fasted state Cohort 3: a single oral dose of 10 mg LY2165766 on Day 1 in the fasted state Cohort 4: a single oral dose of 20 mg LY2165766 on Day 1 in the fasted state Part C Cohort 1: a multiple dose of 6 mg LY2165766 on days 1 - 7, in the fasted state

Procedures: pain, light bleeding, heamatoma, possibly an infection
Medication: balance and tremors (shaking), reduced appetite, increase blood
pressure, enlargement of breast