Assessment of [11C]ER176 to Image Translocator Protein in Brain and Whole Body of Healthy People

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 [(11)C]PBR28 as a positron emission tomographic (PET) radioligand to bind to TSPO
and measure its density. Although [(11)C]PBR28 has high in vivo specific signal, it is very
sensitive to the high and low affinity states of TSPO, which are caused by the rs6971 single
nucleotide polymorphism (SNP) in the fourth exon of the TSPO gene resulting in a
nonconservative alanine-to-threonine substitution in position 147 of the encoded TSPO
protein. 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 [(11)C]PBR28. We recently developed a new TSPO ligand
ER176, the affinity of which differs by only 1.2 fold and therefore LL carriers should
provide measureable brain uptake. The purpose of this study is to assess the potential of
[(11)C]ER176 to image TSPO in brain, characterize its binding sensitivity in lung of healthy
subjects from all three genetic groups, and to do whole-body imaging for biodistribution and
estimation of radiation dosimetry in humans.

The present protocol will use a new PET ligand [(11)C]ER176 to 1) perform an initial
whole-body scan after [(11)C]ER176 injection in a single healthy volunteer to confirm
wide-spread distribution of radioactivity to different body organs (Phase 0); 2) perform
kinetic brain scans in healthy volunteers of 3 different genotypes, with about half of these
volunteers undergoing lung scans in the same session (Phase 1), and; 3) perform whole-body
imaging in healthy volunteers (Phase 2).

This study will assess the relative robustness of absolute quantitation of TSPO in the brain
of healthy subjects, using an arterial input function and pharmacokinetic modeling. In
addition, lung imaging will provide in vivo binding sensitivity of [(11)C]ER176 to TSPO
genotype. Furthermore, the whole-body imaging would estimate the radiation-absorbed doses
for future use of [(11)C]ER176 in clinical studies.

Study Population

We will select up to 36 healthy adult female and male volunteers (age 18 and older) of 3
different TSPO genotypes for brain imaging, and up to 11 additional healthy volunteers for
whole body dosimetry analysis.

Design

For absolute quantification of TSPO, up to 36 healthy controls (up to 12 each of three TSPO
genotypes) will have brain PET imaging using [(11)C]ER176 and these subjects will have the
arterial line and a brain MRI scan. In about half of those subjects from each genotype
group, lungs will be scanned in the same session. For radiation dosimetry of [(11)C]ER176,
up to 11 subjects will have whole-body PET imaging. These subjects will not have arterial
line and MRI scans.

Outcome Measures

The primary outcome measures are: (a) To assess absolute quantitation of TSPO with
[(11)C]ER176, we will determine the identifiability and time stability of distribution
volume in the brain calculated with compartmental modeling. The difference in mean
distribution volumes among subjects with different genotypes would be used to evaluate the
genotype sensitivity of [(11)C]ER176. (b) To assess whole-body biodistribution and dosimetry
of [(11)C]ER176 we will use the organ time-activity curves.

As secondary outcome measure, we will examine the effect of polymorphism on [(11)C]ER176
binding in lungs because lungs have much higher density of TSPO and may be more effective to
show whether ER176 is sensitive to the SNP.

- INCLUSION CRITERIA:

- Age 18 or older.

- Able to give written informed consent.

- Healthy based on medical history, physical examination and laboratory testing.

EXCLUSION CRITERIA:

- 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.

- Drug/alcohol abuse or dependence

- Current use of prescription or chronic (more than 3 continuous weeks) use of
over-the-counter medications for pain, fever or other inflammation including
prednisolone (Orapred), aspirin (Ecotrin), ibuprofen (Advil), and acetaminophen
(Tylenol). The medications will be reviewed to see if subject can be in the study. If
the subject is taking any medication that is not permitted, he/she may be in the
study if the medication can be safely stopped for three weeks. The subject s primary
care doctor will be contacted to stop a medication if necessary. A written permission
will be obtained from the subject to contact his/her doctor.

Please note that exclusion criteria for the dosimetry subjects are the same reported
above, except for MRI contraindications, because an MRI will not be performed in these
subjects.