Study of [11C]DPA-713 for Temporal Lobe Epilepsy

OBJECTIVE:

Translocator protein 18 kDa (TSPO) is highly expressed in activated microglia and reactive
astrocytes in brain, and it may, thereby, be a useful biomarker of neuroinflammation. We
developed [11C]PBR28 as a positron emission tomographic (PET) radioligand to bind to TSPO and
measure its density. The purpose of this study is to assess a new TSPO radioligand,
[11C]DPA-713, and to compare it with [11C]PBR28.

Although [11C]PBR28 has high in vivo specific signal, it is very sensitive to the high and
low affinity states of TSPO, which are caused by a single nucleotide polymorphism (SNP) in
the fourth exon of the TSPO gene. This co-dominant mutation yields three genetic groups: HH,
HL, and LL, where H is the high-affinity form and L is the low affinity form. The frequency
of the L allele is approximately 30%; thus, the frequency of the LL homozygote is
approximately 9%. The affinity of PBR28 to H and L forms differs about 50 fold; thus, LL
carriers provide no measureable signal in brain from [11C]PBR28. In contrast, the affinity of
DPA-713 differs by only four-fold and LL carriers provide measureable brain uptake, although
diminished in comparison to HH and HL carriers.

We recently reported that [11C]PBR28 binding is increased in epileptogenic mesial temporal
lobe in HH and HL carriers, using the ratio of brain uptake in ipsilateral and contralateral
regions. This study will compare [11C]DPA-713 and [11C]PBR28 in two ways. First, what is the
relative robustness of absolute quantitation of TSPO in healthy subjects and patients with
epilepsy, using an arterial input function and pharmacokinetic modeling? Second, what is the
relative sensitivity of [11C]DPA-713 and [11C]PBR28 to detect the seizure focus in patients
with epilepsy and measured as the ratio of brain uptake ipsilateral and contralateral to the
seizure focus.

STUDY POPULATION

This protocol will study a total of 30 patients with epilepsy and 30 healthy human volunteers
using [11C]DPA-713. Studies with [11C]PBR28 in the same subjects will be performed under
other protocols, including 12-N-0182 ( Positron emission tomography measurement of
neuroinflammation and P-glycoprotein in localization-related epilepsy, PI: W. Theodore).

DESIGN

For absolute quantification of TSPO, 10 patients with epilepsy and 25 healthy controls will
have arterial blood sampling concurrent with PET imaging using [11C]DPA- 713. Scans of
healthy subjects will also be used to study effect of the polymorphism to the binding of
[11C]DPA- 713. The subjects will choose to undergo the PET scan with or without the arterial
line. Most, but not all, subjects will also have a scan with [11C]PBR28 under another
protocol. LL homozygotes would be excluded from [11C]PBR28 but would be included with
[11C]DPA- 713.

For detection of increased TSPO receptor binding in epileptogenic foci as a ratio of
ipsilateral to contralateral regions, about 20 patients with epilepsy will be studied with
[11C]DPA-713. Since the ratio of brain uptake will also be obtained as part of absolute
quantitation in ten patients, this ratio of brain uptake will require an additional ten
subjects, who would not require an arterial catheter.

To account for dropouts and data variability, we request a ceiling of 30 epilepsy patients
(about 10 of whom will have an arterial line) and 30 controls. All subjects will have blood
drawn to genotype the TSPO SNP and to perform in vitro radioligand binding to TSPO on
lymphocytes.

OUTCOME MEASURES

To assess absolute quantitation of TSPO with [11C]DPA-713, we will primarily use two outcome
measures: the identifiability and time stability of distribution volume calculated with
compartmental modeling. By comparing data of HH, HL, and LL, we will also estimate
nondisplaceable distribution volume. To assess the sensitivity of [11C]DPA-713 to localize
the epileptogenic focus, we will compare ratio of brain uptake in medial temporal lobe,
ipsilateral and contralateral to the seizure focus.

- INCLUSION CRITERIA:

For healthy volunteers

- Age 18 or older.

- Able to give written informed consent.

- No prior diagnosis of drug or alcohol abuse or dependence.

For patients

- Age 18 or older.

- Able to give written informed consent.

- Having clinically documented partial seizures with consistent EEG evidence as defined
by the 1981 International Classification of Epileptic Seizures, which may be
refractory or responsive to standard antiepileptic treatment. This criterion will be
established by preliminary screening in the NINDS Clinical Epilepsy Section outpatient
clinic under protocol 01-N-0139, and if necessary, inpatient video-EEG monitoring.
Seizure focus localization will be determined by standard clinical, neurophysiologic,
and imaging studies.

- Negative toxicology testing at the time of screening.

- No prior diagnosis of drug or alcohol abuse or dependence.

EXCLUSION CRITERIA:

For healthy volunteers

- Any current Axis I diagnosis.

- Clinically significant laboratory abnormalities.

- Positive test for HIV.

- Unable to have a MRI scan.

- History of neurologic illness or injury with the potential to affect study data
interpretation.

- History of seizures, other than in childhood and related to fever.

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

- Inability to lie flat on camera bed for at least two hours.

- Pregnancy or breast feeding.

- Able to get pregnant but does not use birth control.

- Drug/alcohol abuse or dependence

For patients

- Previous radiation exposure (X-rays, PET scans etc.) that, together with study
procedures, would exceed NIH RSC research limits.

- Claustrophobia to a degree that the subject would feel uncomfortable in the MRI
machine.

- History of brain disease other than epilepsy.

- Cannot lie on their back for at least two hours.

- Known cause for seizures, other than mesial temporal sclerosis, such as tumor or
infection.

- Serious medical illness, other than epilepsy.

- Clinically significant laboratory abnormalities.

- Positive test for HIV.

- Brain abnormality such as a brain tumor, stroke, brain damage from head trauma or
blood vessel abnormalities, on an MRI scan.

- Pregnancy or breast feeding.

- Able to get pregnant but does not use birth control.

- Risk for MRI scan, such as a pacemaker or other implanted electrical devices, brain
stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of
a large artery), metallic prostheses (including metal pins and rods, heart valves, and
cochlear implants), permanent eyeliner, implanted delivery pump, or shrapnel
fragments. Welders and metal workers are also at risk for injury because of possible
small metal fragments in the eye of which they may be unaware.

- For drug-responsive subjects: occurrence of a seizure within the last three months.

- Drug/alcohol abuse or dependence