PET Imaging of Alpha-Synuclein Fibril Formation

Información del proyecto

PET-AlphaSy

Identificador del acuerdo de subvención: 813528

DOI

10.3030/813528

Proyecto cerrado

Fecha de la firma de la CE 30 Agosto 2018

Fecha de inicio 1 Septiembre 2018

Fecha de finalización 30 Noviembre 2022

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 4 100 369,95

Aportación de la UE

€ 4 100 369,95

Coordinado por

KOBENHAVNS UNIVERSITET
Denmark

Periodic Reporting for period 2 - PET-AlphaSy (PET Imaging of Alpha-Synuclein Fibril Formation)

Período documentado: 2020-09-01 hasta 2022-11-30

Resumen del contexto y de los objetivos generales del proyecto

Parkinson’s disease (PD) is a devastating neurodegenerative movement disorder. Like other neurodegenerative disorders, PD is afflicted by problems with early diagnosis as well as a lack of effective means for monitoring both disease progression and the effects of treatment. Development of a Positron Emission Tomography (PET) tracer to both monitor efficacy of novel therapeutics as well as use for earlier diagnosis, would improve the potential for development of better treatments against PD immensely. Development of such a PET tracer requires skilled radiopharmaceutical scientists with a multidisciplinary approach. Our consortium consists of the necessary expertise to develop such a PET tracer. Our overall goals are: 1) Development of an α-synuclein (α-syn) PET tracer to monitor Parkinson’s Disease (PD) therapeutic trials, or to diagnose PD at an earlier stage than currently possible (scientific objective). 2) Training of the next generation of radiopharmaceutical scientists to close the gap of existing to required numbers (training objective) and encourage entrepreneurship within the growing radiopharmaceutical market.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

In WP1, α-syn selective PET based on biologics are developed. Monoclonal antibodies (mAbs) have been labelled with the long-lived radionuclides such as Zr-89. Currently, these mAbs are evaluated in vivo for their ability to image targets beyond the blood-brain-barrier (BBB). In a second approach, pretargeting using bioorthogonal chemistry is used to image mAbs in vivo which have already accumulated at their target sites. We modified these mAbs will with with trans-cyclooctene (TCO) and evaluated their binding profile in vitro. mAbs tolerate up to 15 TCOs. WP1 has proceeded as planned. Chemical synthesis, modification and first labelling experiments have been carried out and have resulted in < 5 publications. We have developed the first pretargeted imaging approach over the blood-brain barrier.

WP2 aimed to develop a small molecule PET tracer targeting α-synuclein. The first period was used to explore 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, synthesized and their selectivity profile determined. 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. We have filed two patents and will publish > 3 papers in 2023.

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

In Europe, 1.6 % of the population aged ≥ 65 and up to 3 % after the age of 80 suffers from PD [1]. As the average age of the population in the EU continues to rise, the overall number of people with PD is increasing [2] and will place a significant burden on society due the associated healthcare costs. Currently, the combined direct and indirect cost of PD, including treatment, social security payments and lost income from inability to work, is estimated to be nearly $25 billion per year in the United States alone.

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.

We have succeeded with identifying several lead structures that can potentially be used to image α-syn. Patent applications have been filed. In vivo in-depth evaluation is currently on-going. Furthermore, we have developed the first pretargeted imaging approach to target nanomedicines beyond the blood-brain barrier.


[1]J. Neurol. Neurosurg. Psychiatry 1997, 62, 10 and Neurol. Clin. 1996, 14, 317
[2] Neurology 2007, 68, 384

Group photo PET-AlphaSy ITN

Logo PET-AlphaSy