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.