Tandem 6: Development of New Tracers for Atherosclerosis Imaging

Short Summary:

We use PET/CT to develop and assess the potential of newly designed radiopharmaceuticals for their capacity to distinguish between stable and unstable atherosclerotic plaques in a non-invasive manner.

Scope:

Spontaneous ruptures of carotid and coronary plaque are the main cause of stroke and myocardial infarction in our society. Currently the most widely used compound to image inflammation is 18F-labeled Fluoro-deoxyglucose (FDG), which unfortunately shows to unspecific accumulation for specific unstable plaque targeting. Thus, there is a clinical need to delineate between stable and unstable atherosclerotic plaques preferentially in a non-invasive manner using Positron Emission Tomography.

Specific Aims:

The folate receptor subtype beta known to be expressed by activated macrophages in plaques. In experimental animals, selective uptake of fluorescent folate conjugates has been found in atherosclerotic plaques. Recently, an 18F-labeled folate conjugate (FFA) has been synthesized in the Center for Radiopharmaceutical Science ETH (Ross et al., 2008) and optimized for tumor receptor imaging (Ross et al., 2010). Modifications with regard to optimized synthesis yield, lack of toxicity, and human-grade GMP production will make this a suitable compound for promising “first in human” evaluation. We will clinically assess FFA targeting for its capacity to distinguish between stable and unstable plaques and compare these data to FDG.

Molecular imaging techniques used:

18F-FFA will be evaluated by autoradiography in a human tissue exvivo model based on material from carotid endarterectomy as previously established (Pedretti et al., 2010; Fiechter et al., 2011). Thereafter, in vivo human studies with 18F-FFA will be performed with PET/CT.

Consecutive sections of human carotid plaques from endarterectomy surgeries are analyzed by histology (A), immunohistochemistry (B) and in vitro autoradiography (C). (Müller et al., 2014)
In a shear-stress induced atherosclerosis mouse model a non-constrictive (B left) and on the contralateral side a constrictive cuff (A, B right) is placed around the carotid artery. CT (C) and PET (D) scans in mice with [18F]FDG show inflammation in the cuff regions 8 days after surgery. Surgery-induced inflammation disappears with time and atherosclerotic plaques develop within 6 weeks after surgery. B from Kuhlmann et al., Journal of Visualized Experiments, DOI : 10.3791/3308, 2012

Added value of KFSP for this specific tandem project:

The KFSP will allow to take a short cut for closing the gap from bench (new FFA compounds from ETH) to bedside (clinical PET/CT) as FFA can be tested in human tissue and potentially be translated directly into a clinical human application study.

References