Evaluation of the ?-synuclein PET radiotracer (d3)-[11C]MODAG-001 in pigs

Background: A positron emission tomography (PET) radiotracer to neuroimage alpha-synuclein aggregates would be a crucial addition for early diagnosis and treatment development in disorders such as Parkinson's disease, where elevated aggregate levels are a histopathological hallmark. The radiotracer (d3)-[11C]MODAG-001 has recently shown promise for visualization of alpha-synuclein pre-formed fibrils (alpha-PFF) in rodents. We here test the radiotracer in a pig model where proteins are intracerebrally injected immediately before scanning. Four pigs were injected in one hemisphere with 150 mu g alpha-PFF, and in the other hemisphere, either 75 mu g alpha-PFF or human brain homogenate from either dementia with Lewy bodies (DLB) or Alzheimer's disease (AD) was injected. All pigs underwent one or two (d3)-[11C]MODAG-001 PET scans, quantified with the non-invasive Logan graphical analysis using the occipital cortex as a reference region. Results: The alpha-PFF and AD homogenate injected brain regions had high uptake of (d3)-[11C]MODAG-001 compared to the occipital cortex or cerebellum. BPND values in 150 mu g alpha-PFF injected regions was 0.78, and in the AD homogenate injected regions was 0.73. By contrast, the DLB homogenate injected region did not differ in uptake and clearance compared to the reference regions. The time-activity curves and BPND values in the 150 mu g and 75 mu g injected regions of alpha-PFFs show a dose-dependent effect, and the PET signal could be blocked by pretreatment with unlabeled MODAG-001. Conclusion: We find that both alpha-PFF and AD brain homogenates give rise to increased binding of (d3)-[11C] MODAG-001 when injected into the pig brain. Despite its limited specificity for cerebral alpha-synuclein pathology, (d3)-[11C]MODAG-001 shows promise as a lead tracer for future radiotracer development.

Automated summary

This study tested the effectiveness of a PET radiotracer (d3)-[11C]MODAG-001 in pig brains. Results showed increased binding of the radiotracer after injection of alpha-synuclein aggregates and Alzheimer's disease brain homogenate. Despite limited specificity, this radiotracer shows promise for future radiotracer development.