Evaluation of a Novel PET Radioligand to Image OGA
Condition: Pharmacokinetics; Adult
Study type: Observational

Summary: 
      Background:

      O-GlcNAcase (OGA) is a brain enzyme. It may play a role in brain disorders like Alzheimer s
      disease. Researchers want to see if a new drug can be used with positron emission tomography
      (PET) scans to show OGA better. Researchers want to learn more about how it acts in healthy
      people.

      Objectives:

      To test if the new drug [18F]OGA-1 can measure its receptor. To determine whether the same
      results occur when scanning a person twice.

      Eligibility:

      Healthy adults age 18 and older who are already enrolled in a separate protocol.

      Design:

      Some participants will have 1 whole-body PET scan during one 4-hour visit to the clinic. Some
      will have 2-3 brain scans (PET and MRI) over 2-3 days.

      For the PET scan, a needle will guide a thin plastic tube (IV catheter) into an arm vein. A
      small amount of radioactive chemical will be injected through the catheter. The needle will
      be removed. Only the catheter will be left in the vein.

      Another IV catheter may be placed to draw blood.

      Blood pressure, heart rate, and breathing rate will be measured. Participants will have an
      electrocardiogram.

      Participants will lie on a bed that slides in and out of the donut-shaped scanner.

      The scan will last 2-3 hours.

      For brain PET scan, participants will wear a plastic mask to keep their head still.

      For magnetic resonance imaging (MRI) scan, participants will lie on a table. The table slides
      in and out of the MRI scanner. This is a metal cylinder in a strong magnetic field.
      Participants will be in the scanner up to 1 hour.
    

Detailed description: 
      Objective:

      Tau, a microtubule associated protein, regulates axonal structure and function within neurons
      of the brain. Neurofibrillary tangles contain hyper-phosphorylated, insoluble tau protein and
      are a hallmark of Alzheimer s disease (AD) and other tauopathies. Hyperphosphorylation of tau
      is required for its aggregation into tangles. One novel strategy to decrease the
      phosphorylation of tau is to increase the number of sugar molecules attached to tau, with the
      overly simple mechanism that the presence of the sugar molecules physically blocks
      phosphorylation. In this case, the sugar molecule is N-acetyl-Beta-D-glucosamine (GlcNAc),
      and increased glycosylation is achieved by inhibiting the enzyme (OGA) that removes these
      residues.

      In collaboration with Eli Lilly, our laboratory recently developed (18F)OGA-1, a novel PET
      ligand to image the hydrolase OGA (O-GlcNAcase). Initial PET scans in monkey demonstrated
      that (18F)OGA-1 is a promising ligand.

      This protocol is a first-in-human evaluation of (18F)OGA-1 and has four phases:

        1. Phase 1: whole body imaging of one (1) subject with a low injection activity of
           approximately 2 mCi to confirm that no organ has prominently high uptake of (18F)OGA-1;

        2. Phase 2: kinetic brain imaging in ten (10) subjects with up to 5 mCi injection to
           quantify OGA in brain relative to concurrent measurement of the parent radioligand in
           arterial plasma and venous plasma;

        3. Phase 3: if (18F)OGA-1 is successful in Phase 2 in the first couple of subjects, we will
           estimate the radiation-absorbed doses by performing whole body imaging on a total of
           eight (8) subjects, with 5 mCi injection;

        4. Phase 4: test-retest analysis in twelve (12) subjects, of brain binding relative to
           concurrent measurement of the parent radioligand in arterial plasma (5 mCi per scan) and
           venous plasma.

      Thus, a total of 9 for whole body imaging and 22 for brain imaging

      Study Population:

      Healthy adult female and male volunteers (n= 22, ages greater than or equal to 18) will
      undergo brain imaging. An additional nine healthy volunteers will undergo whole body
      dosimetry analysis, for a total of 31 healthy volunteers.

      Design:

      For quantification of (18F)OGA-1, 22 healthy controls will undergo brain PET imaging using
      [18F]OGA-1 an arterial line, and venous line. Of this group of 22 healthy controls having
      brain PET imaging, twelve of them will have a test-retest scan. Nine additional subjects will
      have a whole body PET scan for dosimetry. For dosimetry, no arterial line will be used.

      <TAB>

      Outcome Measures:

      To assess quantitation of OGA with (18F)GA-1, we will primarily use two outcome measures,
      namely the identifiability and time stability of distribution volume (VT) calculated with
      compartmental modeling. In the test-retest study, we will calculate the retest variability.
      We will assess whole-body biodistribution and dosimetry of (18F)OGA-1 by calculating doses to
      organs and the effective dose to the body as a whole.
    

Intervention name(s): 18F-OGA-1
Intervention type(s): Drug
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Healthy Volunteers
      
Keywords: PET Imaging; Neurodegeneration