Specific PET Radioligand Binding to Translocator Protein

Objective:

The 18kDa Translocator Protein (TSPO, formerly known as the peripheral benzodiazepine
receptor (PBR)) is expressed in activated microglia and reactive astrocyte. It has therefore
been used as an imaging target for positron emission tomography (PET) to investigate diseases
involving microglial activation and/or macrophage recruitment, such as multiple sclerosis,
herpes encephalitis, Parkinson s disease, Alzheimer s disease and ischemic stroke. The vast
majority of PET studies reported to date have used 11C-(R,S) and 11C-(R)-PK 11195, a
3-isoquinolinecarboxamide antagonist, with nanomolar affinity for TSPO. Several second
generation radioligands, including 11C-PBR28, 11C-DPA-713, and 11C-ER176 have been developed.
Although these ligands have greater signal to noise (specific to nondisplaceable uptake)
ratio than 11C-(R)-PK 11195,their binding to TSPO is affected by a single nucleotide
polymorphism (SNP). Specific to nondisplaceable ratio of 11C-PBR28 has recently been
reported. However, no one has ever measured the specific to nondisplaceable ratio of other
TSPO radioligands including 11C-(R)-PK 11195, 11C-DPA-713 and 11C-ER176 in human subjects. In
addition, differences in this binding site between species preclude comparisons based on
studies in animals. The purposes of this study are to measure the signal to noise ratio
(i.e., ratio of specific to non-displaceable uptake) of 11C-(R)-PK 11195, 11C-ER176 and
11C-DPA-713 in human subjects with two scans in each subject: at baseline and after emapunil,
an agonist at the TSPO site and a putative anxiolytic based on studies in animals and in
humans and study the effect of the SNP on the in vivo specific binding of the PET ligands.

Study population:

75 healthy volunteers in total aged 18 to 55 years. Of these, 25 will have 11C-(R)-PK 11195,
25 have 11C-DPA-713 scans, and 25 have 11C-ER176.

Design:

Healthy volunteers (n = up to 25) will have two scanning sessions using 11C-(R)-PK 11195: a)
baseline i.e., medication-free and b) blocking i.e. with medication. For blocking, we will
give one oral dose of emapunil (15 or 90 mg), about 1.5 hours before the second injection of
the radioligand. Both scanning sessions would include an arterial line and measurement of the
input function of parent radioligand separated from radiometabolites as well as plasma free
fraction of radioligand. Additional 25 healthy volunteers will have two scanning sessions
using 11C-DPA-713 in the same design, one baseline and another after one oral dose of
emapunil. An additional 25 healthy volunteers will have two scanning sessions using 11C-ER176
in the same design, one baseline and another after one oral dose of emapunil. The total
number of participants is 75 (= 25 + 25 + 25)

Outcome measures:

Baseline scans measure total binding i.e., total distribution volume (V[T]). By applying the
Lassen plot, combined data from both baseline scans and those with administration of emapunil
measure nonspecific binding i.e., nondisplaceable distribution volume (V[ND]). From these
V[T] and V[ND] values, specific-to-nondisplaceable ratios will be calculated as (V[T] V[ND])
/ V[ND[ and the influence of the SNP to specific binding, V[S] = V[T] - VND will also be
studied.

- INCLUSION CRITERIA:

1. Male or female subjects between 18 to 55 yrs of age and able to give written
informed consent.

2. Subjects must be healthy based on medical history, physical examination and
laboratory testing.

3. Be able to provide own consent.

4. Agree to use contraception for 30 days after emapunil administration.

EXCLUSION CRITERIA:

1. Any past or present Axis I psychiatric disorder. Any history of alcohol or substance
dependence, except nicotine dependence, within the past 6 months

2. Serious medical problems including but not limited to chronic neurological disease
such as multiple sclerosis, autoimmune diseases, or serious cardiopulmonary disease.

3. Active seizure disorder, as defined as having had a seizure in the past year or being
on antiepileptic medications for seizures.

4. Positive HIV test.

5. Recent research-related exposure to radiation (i.e., PET from other research) which
when combined with this study would be above the allowable limits.

6. Metallic foreign bodies that would be affected by the MRI magnet or fear of enclosed
spaces likely to make the subject unable to undergo an MRI scan.

7. Claustrophobia

8. Positive urine drug screen at time of enrollment.

9. Pregnancy at time of scan (beta-HCG will be measured in all female patients within 24
hours before start of scan and must be negative). Lactating women who are breast
feeding.

10. Prescription or over-the counter medication use; psychotropic herb use (e.g., St. John
s Wort).

11. Are not able to comfortably lie flat on the back for at least two and a half hours at
a time