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

A positron emission tomography (PET) radiotracer to neuroimage α-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 α-synuclein pre-formed fibrils (α-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 μg α-PFF, and in the other hemisphere, either 75 μg α-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.

The α-PFF and AD homogenate injected brain regions had high uptake of (d₃)-[¹¹C]MODAG-001 compared to the occipital cortex or cerebellum. BP_ND values in 150 μg α-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 BP_ND values in the 150 μg and 75 μg injected regions of α-PFFs show a dose-dependent effect, and the PET signal could be blocked by pretreatment with unlabeled MODAG-001.

We find that both α-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 α-synuclein pathology, (d₃)-[¹¹C]MODAG-001 shows promise as a lead tracer for future radiotracer development.