Evaluation of a Novel PET Radioligand to Image OGA

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.