INnoVAtive Solution for Imaging of Infiltrating mONocytes

Project Information

INVASIION

Grant agreement ID: 101067635

DOI

10.3030/101067635

Project closed

EC signature date 20 June 2022

Start date 1 August 2022

End date 31 January 2026

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 203 464,32

Coordinated by

STICHTING AMSTERDAM UMC
Netherlands

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

Reporting period: 2022-08-01 to 2026-01-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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.