Pilot Study of [11C]HY-2-15: A Mixed Alpha-Synuclein and Tau PET Radiotracer

Abstract

A novel brain positron emission tomography (PET) radioligand, [¹¹C]HY-2-15, has potential for imaging alpha-synuclein aggregations in multiple system atrophy and misfolded tau proteins in tauopathies, based on its high binding affinity in disease brain tissue homogenates. Here, we demonstrate that [³H]HY-2-15 has the capability to bind to aggregated alpha-synuclein in multiple system atrophy brain and tau aggregations in progressive supranuclear palsy and corticobasal degeneration brain tissues via in vitro autoradiography study. A first-in-human pilot multicenter clinical study recruited a total of 10 subjects including healthy controls and patients with Parkinson's disease, multiple system atrophy, or progressive supranuclear palsy. The study revealed that [¹¹C]HY-2-15 has a relatively higher specific uptake in the pallidum and midbrain of patients with progressive supranuclear palsy. Total-body scans performed on the PennPET Explorer showed the radiotracer was cleared by renal excretion. However, the rapid metabolism and low brain uptake resulted in a limited signal of [¹¹C]HY-2-15 in brain.

Keywords: PET; Parkinson’s disease; multiple system atrophy; progressive supranuclear palsy; radioligand; tau; α-synuclein.

Figure 1

Autoradiography showing total binding using 10 nM [³H]HY-2-15 (upper panel) and non-specific binding (middle panel; determined with addition of 1 μM cold HY-2-15) of postmortem FFPE brain sections containing the cerebellum from MSA-C, the cingulate cortex from MSA-P, PD, DLB, and HC, the frontal cortex from CBD, and the parietal cortex from PSP cases. Autoradiography color/brightness threshold levels are expressed in counts (0–1000). Per MSA-C, MSA-P, PD, DLB, and HC cases, pS129 α-syn IHC (lower panel) was performed on adjacent sections as pathology reference, while for CBD and PSP, AT8 IHC was carried out. pS129, anti-phospho129 α-syn antibody; AT8, anti-phosphorylated tau antibody. Scale bars: 5 mm. MSA-C, multiple system atrophy—cerebellar subtype; MSA-P, multiple system atrophy—parkinsonian subtype; PD, Parkinson’s disease; DLB, dementia with Lewy bodies; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy; and HC, healthy control.

Figure 2

(A) Parent fraction of [¹¹C]HY-2-15 from arterial blood samples. Time–activity curves of pallidum, midbrain, cerebral cortex, and cerebellar cortex in SUV for (B) HC and (C) PSP. Data is presented as mean ± standard deviation. HC, healthy control; PSP, progressive supranuclear palsy; and SUV, standardized uptake value.

Figure 3

Representative 15–35 min [¹¹C]HY-2-15 SUVR image with a whole brain mask of HC, PSP, PD, and MSA-P in the sagittal and axial views of cerebellum, midbrain, and basal ganglia. HC, healthy control; PSP, progressive supranuclear palsy; PD, Parkinson’s disease; MSA-P, multiple system atrophy—parkinsonian subtype; and SUVR, standardized uptake value ratio.

Figure 4

Scatter plot of brain regional [¹¹C]HY-2-15 SUVRs in HC, PSP, PD, and MSA-P. HC, healthy control; PSP, progressive supranuclear palsy; PD, Parkinson’s disease; MSA-P, multiple system atrophy—parkinsonian subtype; and SUVR_Cb, standardized uptake value ratio using cerebellar cortex as reference region.

Figure 5

Biodistribution of [¹¹C]HY-2-15. (A) Time–activity curves of %ID in brain and peripheral organs. (B) Total-body SUV image of 7–11 min, 20–30 min, and 80–90 min post [¹¹C]HY-2-15 injection in the two different coronal views of a healthy control subject. SUV, standardized uptake value; and %ID, percent injected dose.