PET aSyn vendor matrix (AC Immune / MODAG / University of Zurich / QST / Shenzhen / Merck / Mass Generic at Brigham) — Lead compound, Derivative, Structure, patient, Timeline, detects, in vitro Saturation binding affinity, IF, ARG, Preclinical Tox start
PET aSyn vendor matrix
| AC Immune | MODAG | University of Zurich | QST (Takeda, QST, Eisai, and Ono) | Shenzhen | Merck | Mass Gener at Brigham | ||
|---|---|---|---|---|---|---|---|---|
| Lead compound | ACI-3847 / ACI-12589 / ACI-15916 | SPAL-T-6 | C05-05 / SPAL-T-95 | FOSO28 | MK-7337 | |||
| Derivative of what? | Pbb3 (a tau protein pet tracer) | benzothiazole-benzofuran-phenol derivative | ||||||
| Structure | (Smith, 2023 #2765), Not found in cortells | NYBB 2023/0840 wo etc | ||||||
| Timeline | FY2020 4Q FH DLB/PD w/ or w/o A6 and tau | Not prioritized | 2nd FH candidate (One 2021 #2305) | (Xiang, 2023 #2397) A FH to begin in 2023 | preparation tracer for use; In to humans 2023, In trials | |||
| detects | Morphomer platform 일정 thioflavin (oligo) PFF (recombinant 일정) oligomers with 2-6 nM | bind fibril forms of α5 but not soluble monomeric form because the series comes from β-sheet binder candidate 잡고 PFF (오리고머 fibril/Monomer ratio etc); (screening) aSyn PFF; candidate aSyn PFF tracer (PFF/Monomer ratio etc) | ||||||
| Current homeostates / in vitro (source?) / Saturation binding affinity | Saturation binding affinity, with values of 4 nM and 22 nM brain homogenates from people with PD and MSA respectively. Kd: 18-35nM (PM) | 5-1) Homologous binding with brain homo, fig30 DLB brain homogenates: CC50-1.58 IC50-10.86 AAA before 3-1 DLB brain homogenates of MSA-P putamen: 1 (affinity-binding) homologues of MSA-P 2.4 BnM ii) (selectivity) the blind binding was inhibited by neither cilengitide a MAO-A inhibitor (red symbols), nor selegiline a MAO-B inhibitor (green symbols) at varying concentrations. | 1) IF in patient brain sections (Selectivity α-syn preferred (αSyn vs tau) ie [αsyn] AGE α-syn aging fluid 1) IF in vivo 2-photon microscopy in PFF injected mouse brain ; aSyn 약 30nM 일정 인 일정 propose 비교 의용 / IF compared to NHP-aSyn fix | (Xiang, 2023 #2397) IC: 2-6-50nM patient (PD vs HC vs AS); HCl only 1.2x [no quantification] | (Matsuoka, 2022 #2127) figs MSA-P patient brain section a Kd PFF (no quantification); These sections were then used for fluorescence staining with non-radio-labelled SPAL-T-06 (30µM) and pcl129 revealing ABUNDANT pcl in the putamen of the MSA-P case (no quantification) | 1) IF in patient brain sections (familial PD : DLB ; PDD MSA: distribution in these brain sections matched IHC of α-asyn; suggesting that the tracer binds its target a Kd of 17 nM cortex of PD 30 nM cell MSA) | ||
| IF | This tracer bound to brainstem and midbrain sections in people with MSA AND DLB; as well as cerebellar white matter in people with MSA; [No labeling] (Matsuoka, 2022 #2127) figs MSA-P patient brain section was Kd PFF (no quantification); Cell sections then used for fluorescence staining with non-radiolabeled SPAL-T-06 (30µM) and pcl129; revealing ABUNDANT pcl in the putamen of the MSA-P case (no quantification) | |||||||
| ARG | vs HC; Cold (-); Hot (HCl only 1.2x); Cold; (A30P mice Kd 0.917nm Bmax 30nM); FIG1 IF AAV α-asyn mice patient (MSA DLB) FIG3 IF WT mice 5xFAD Tau P3015 AAV-α-asyn AS3T mice α-injected FOSO28 (2 quantification); mouse striatum → PET scan of (PFF mice and PFF NHP) (marmosette); (Ono 2021 #2305) C11-MODAG-001 in the entered brain & midbrain sections compared to a... fight ASYN PFF in 'aged ASYP α-syn neuron-specific binding signal that overlaps with α-syn pathology in the medium and brain stem of MSA mouse SUVR signal | |||||||
| ARG / desirable PK characteristics in NHP | ||||||||
Preclinical Tox (start)
- [non-GLP] Two studies in rat
(plus a partial line or tangle accumulation.)