INnoVAtive Solution for Imaging of Infiltrating mONocytes

Información del proyecto

INVASIION

Identificador del acuerdo de subvención: 101067635

DOI

10.3030/101067635

Proyecto cerrado

Fecha de la firma de la CE 20 Junio 2022

Fecha de inicio 1 Agosto 2022

Fecha de finalización 31 Enero 2026

Financiado con arreglo a

• Marie Skłodowska-Curie Actions (MSCA)

Coste total

Sin datos

Aportación de la UE

€ 203 464,32

Coordinado por

STICHTING AMSTERDAM UMC
Netherlands

Periodic Reporting for period 1 - INVASIION (INnoVAtive Solution for Imaging of Infiltrating mONocytes)

Período documentado: 2022-08-01 hasta 2026-01-31

Resumen del contexto y de los objetivos generales del proyecto

The societal burden of brain disorders, such as multiple sclerosis(MS), Alzheimer’s and Parkinson’s disease is enormous and is considered one of the world’s most important health challenges. They affect millions of people worldwide and the annual healthcare costs are high and are increasing with the aging population. There is an immediate need to better understand the underlying molecular mechanisms of these disorders. Inflammation is widely recognized to play an important role in many neurological disorders. Next to the response of microglia, the resident immune cells in the central nervous system (CNS), infiltration of monocytes from the blood occurs, but the exact role of monocyte infiltration and the interplay between microglia and monocytes in vivo is still largely unknown. Clinical trials with chemokine receptor type 2 (CCR2) antagonists, aiming to reduce recruitment of monocytes and thereby reducing neuroinflammation, do not show clinical efficacy. Together, this emphasizes the need to unravel the role of infiltrating monocytes in human disease in vivo. Positron emission tomography (PET) is an imaging technique well suited to serve this purpose, but this requires development of a suitable, brain-penetrant PET tracer targeting CCR2. A successful PET tracer will contribute to a better understanding of monocyte infiltration in disease in vivo and could ultimately serve as an important tool to guide drug development and evaluate novel disease-modifying therapies and therapies inhibiting monocyte infiltration.

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

Immunohistochemical staining on spinal cord of a rat model of multiple sclerosis (EAE) revealed markedly increased expression of CCR2 in diseased rats compared with control and fully recovered rats. These results demonstrate viability of CCR2 as target for PET imaging in EAE/MS. To finalize target validation, a suitable PET tracer is required for in vitro autoradiography studies. Precursors for radiolabeling have been synthesized, and first radiolabeling experiments to obtain [11C]AZD2423 via [11C]CO2 fixation was successful. Additionally, two new lead compounds have been identified in silico, for which synthesis of precursors for radiolabeling is ongoing.

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)

Preclinical target validation of CCR2 as a potential target for brain PET is in the final stages. While target binding studies in EAE rat brain tissues with [11C]AZD2423 are planned, ongoing efforts aim to further advance the development of brain penetrating CCR2 targeting PET tracers.