Periodic Reporting for period 1 - PET-AlphaSy (PET Imaging of Alpha-Synuclein Fibril Formation)
Reporting period: 2018-09-01 to 2020-08-31
WP2 aims to develop a small molecule PET tracer targeting α-synuclein. The first period was used to explored several leads and design improved analogues, based on lessons learned from literature. SIL and Anle compounds are the most promising structures. Several analogues of both SIL and ANLE are prepared for tritiation. Ten additional lead structures have been identified and synthesize. They are currently used to determine their selectivity profile. Moreover, a new approach is initiated to develop α-synuclein selective peptide-based tracers. Respective structures were identified using known binding sites of α-synuclein to several proteins. The key binding motif has been identified and first peptide-based targeting moieties will be synthesized soon.
WP3 is focusing to develop evaluation strategies for tracers developed in WP2/3.First in vitro assays including in vitro autoradiography on human brain sections and saturation/ competition binding assays on recombinant α-syn preformed fibrils will be established and used as the first stage of evaluation for small molecule-based/antibody-based radioligands. The intracranial deposition model has been established at all sites and the in vitro binding assays based on synthetic α-synuclein fibrils is also established and evaluated, and thus ready to be implemented in all partner labs that require it. Human brain tissue from different α-synucleinopathies and controls have been acquired from the Dutch brain bank and will now be distributed to the consortium and used for binding studies with the novel radioligands.
This consortium aims to develop PET tracers targeting α-syn, the hallmark for PD. These tracers will make it possible to image disease-modifying approaches, diagnose and study PD and related diseases and in a completely new fashion. We will establish pre-targeted imaging for mAbs that are capable to reach targets beyond the BBB. This is currently not state-of-the-art, but desperately needed.
Success will lead to earlier and accurate PD diagnosis. Tracers will also be applied to validate novel therapeutic approaches early in the drug development phase and reduce drug development costs. Ultimately, success of our research ideas leads to economic growth in the EU and make our healthcare system sustainable.
J. Neurol. Neurosurg. Psychiatry 1997, 62, 10 and Neurol. Clin. 1996, 14, 317
 Neurology 2007, 68, 384