Development of a Novel Glutamate Receptor Ligand for PET Scans in Neuropsychiatric Systemic Lupus Erythematosus

Neuropsychiatric lupus is comprised of numerous, complex central and peripheral nervous
system symptoms whose pathophysiologic mechanisms remain poorly understood. Cross-reactive
anti-dsDNA antibodies have been shown to bind NR2A/NR2B subunits of the N-methyl D-aspartate
receptor (NMDAR) on neurons and synergize with glutamate in a concentration dependent manner
to either modulate receptor function or cause an excitotoxic, non-inflammatory neuronal
death. Mice immunized to express anti-NMDAR Aab demonstrate a causal relationship between
anti-NMDAR Aab and persistent behavioral and cognitive neuropathology following compromise to
the blood brain barrier (BBB) which is necessary for Aab access to the brain.

The investigators' previous cross-sectional FDG-PET studies of resting brain glucose
metabolism demonstrate robust hypermetabolism in the hippocampus of SLE subjects that
associates independently with serum Anti-NMDAR Aab titer and impaired memory. Moreover, the
combination of hippocampus hypermetabolism and elevated serum titers of Anti-NMDAR Aab has a
higher predictive value for memory impairment than either variable alone. These significant
correlations must be tested in a longitudinal study to evaluate the utility of FDG-PET as a
biomarker for Anti-NMDAR Aab-mediated brain damage. The proposed longitudinal studies will
inform the investigators about correlates of cognitive and behavioral change over time using
FDG-PET imaging (Aim 1). Additionally, the investigators will explore NMDAR biology with a
novel PET ligand, [11C]-CNS5161, used to localize and quantify NMDAR activation (Aim 2) and
explore the role of blood brain barrier (BBB) integrity in cognitive and behavioral
impairment (Aim 3).

Inclusion Criteria:

1. Must be ≥18 and ≤55 years of age.

2. Must fulfill the current American College of Rheumatology (ACR) revised criteria for
the diagnosis of SLE.

3. Must be willing and able to sign informed consent.

4. Must have stable disease activity and medication doses for 8 weeks prior to screening.

Exclusion Criteria:

1. History of neurological diseases including head injury resulting in a loss of
consciousness, strokes (secondary to hypertension, atherosclerosis, diabetes),
seizures, toxic exposure, any difficulties at birth, mental retardation.

2. History of documented transient ischemic attacks within six months of screening.

3. Currently taking anti-convulsant medication.

4. Limited fluency with English that in the opinion of the investigator would limit the
subject's performance on the ACR battery of cognitive tests or the N-back task chosen
for the working memory task during the PET scan.

5. History of illicit drug use (cocaine, cannabis, heroin) that can result in altered
cognition.

6. Increased disease activity within 8 weeks defined by an increase in SLEDAI by 3 points
or more, exclusive of points from serologies.

7. Any increase in steroid dose or addition of disease modifying agents within 8 weeks.

8. Exceeding the weight limit on the MRI scanner.

9. Suffering from claustrophobia.

10. Have any of the following: cardiac pacemakers, auto defibrillators, neural
stimulators, aneurysm clips, metallic prostheses, cochlear implants, any implanted
devices (pumps, infusion devices, stents), permanent eye make-up, IUD's, shrapnel
injuries.

11. Current use of anxiolytic, antidepressant or antipsychotic medications.

12. Pregnant and/or lactating women

13. A glomerular filtration rate less than ≤60 mL/min or any evidence of active renal
disease from any cause that would put the subject at risk for increased toxicity from
gadolinium contrast for the MRI study.

14. The presence of uncontrolled or severe hypertension, diabetes mellitus or liver
disease that would increase the risk of increased toxicity from gadolinium contrast.