Assessment of the Effect of Sertaline on the Specific Binding of 123-I MZINT in Healthy Subjects

Serotonin (5-HT) is a monoamine neurotransmitter found in the peripheral and central nervous
system. It is responsible for regulating a wide variety of physiological processes and higher
CNS functions. 5-HT neurons project diffusely throughout the brain, innervating the cerebral
cortex, hippocampus, thalamus, midbrain, brainstem and cerebellum, and play a prominent role
in regulating physiological and behavioral responses such as arousal, thermoregulation,
anxiety, and affect.

All subjects will undergo written informed consent and a screening evaluation including
baseline clinical laboratory testing, and a baseline physical and neurological evaluation.
healthy subjects will undergo a baseline 123-I MZINT injection and SPECT imaging described
below. At baseline, healthy subjects will be started on either no treatment (n=4), or one of
three different doses of sertraline (25 mg/day n=2, 50 mg/day n=2 or 150 mg/day n=2), which
will be administered over a 14 day period. Fourteen days following imaging session 1, all
subjects (treated with sertraline and untreated) will undergo a second 123-I MZINT and SPECT
imaging study. Data from the baseline and follow-up SPECT images will be compared to evaluate
for any effect of sertraline on regional brain uptake of 123-I MZINT. The subjects that are
randomized to no treatment will serve as controls and provide preliminary test-retest
reproducibility data on the imaging outcome measure.

The goal of this proposal is to evaluate the effect of sertraline administration on the
specific [123-I] mZINT. In vitro and in vivo data from early human studies and baboon studies
strongly support further evaluation of [123I] mZINT in healthy subjects.

Inclusion Criteria:

- The subject is aged 18-70.

- Written informed consent is obtained.

- The participant has no clinically significant clinical laboratory value and/or
clinically significant unstable medical, neurological or psychiatric illness.

- For females, non-child bearing potential or negative urine pregnancy test on day of
[123I] mZINT injection.

- Willingness to comply with the study protocol

Exclusion Criteria:

- The subject has a clinically significant clinical laboratory values abnormality,
and/or medical or psychiatric illness.

- The subject has any disorder that may interfere with drug absorption, distribution,
metabolism, or excretion (including gastrointestinal surgery).

- The subject has evidence of clinically significant gastrointestinal, cardiovascular,
hepatic, renal, hematological, neoplastic, endocrine, neurological, immunodeficiency,
pulmonary, or other disorder or disease.

- Use of all prescription drugs or non-prescriptions drugs that may effect serotonin
such as antidepressants including sertraline, fluoxetine, fluvoxamine, venlafaxine
within 60 days of baseline imaging study.

- The participant has a history of alcohol, narcotic, or any other drug abuse as defined
by the Diagnostic and Statistical Manual of the American Psychiatric Association, 4th
Edition (DSM IV) {American Psychiatric Association, 1994 #2} within the past 2 years.

- Pregnancy