List of questions

Which imaging biomarkers could be developed to diagnose patients with migraine? Can these be combined with other biomarkers?

migraine is a common neurological disorder affecting appr 10% of the adult population; and in the chronic form with 15 or more headache days per month affecting 1-2,5% of the population.
since diagnosis / treatment is mostly symptom-based, it would be very valuable ot have eg biomarkers to diagnose and facilitate possibilities to provide specialis treatment to patients earlier.

What is the utility of FDG for monitoring drug treatment in inflammatory diseases, which novel methods for specific imaging in inflammation are available or under development and which targets should be selected for new developments of inflammation imaging modalities?

1. What is the utility of FDG for monitoring drug treatment in inflammatory diseases?
Which novel methods for specific imaging in inflammation are available or under development?
Which targets should be selected for new developments of inflammation imaging modalities? What path can we take in order to optimally develop, characterize and take new molecular imaging methods efficiently to the clinic?

Background:
There is a significant need in early drug development to be able to monitor quantitatively and repetitively the effects of drugs in inflammatory disease. Blood biomarkers are important but may not always reflect the effects at specific sites of inflammation and have not the possibility to fully assess diseases with heterogeneous extent such as Rheumatoid Arthritis with potential heterogeneous responses.
Imaging with PET and FDG is emerging as a potential to monitor disease activity across all sites in the body, and to give quantitative values supposedly related to local inflammatory activity. However, current understanding suggests that the FDG uptake is contributed to by multiple cell types including macrophages, granulocytes, activated fibroblasts and potentially by reactive epithelium. The method might still have a value in treatment monitoring, but there is a desire to have available imaging methods which are more specific to certain populations of immune cells which the drug is targeting.
Therefore the search for more specific methods and more specific targets is encouraged on a development path towards human imaging which can be applied to characterize the effects of novel drugs on specific immune cell populations such as M1- or M2-macrophages or subtypes of T-cells.
The process of probing novel tracers up to humans seems at present slow and complex – how can we speed it up? Are pre-competitive alliances the answer, networks across academic centres? What is Pharma’s role in this?

How shall we design studies and analyse the results in imaging with radiolabelled biologics in order to understand target access and target saturation and how do we best model imaging results of tissue concentration and its time course and dose-dependence in complement to plasma PK?

PBPK modelling is well advanced and an important tool in predicting biodistribution and extrapolate knowledge of plasma PK towards tissue exposure as well as defining ranges of variability in patient populations.
Biodistribution imaging in humans using radiolabelled biologics is emerging as an important component in drug development, potentially allowing direct visualization and measurements of tissue concentration and its time course.
Combining the tissue PK from an imaging study with plasma PK gives an opportunity to define rates and magnitude of drug extravasation as well as giving indications of further cellular processes like receptor binding and internalization. Finally, by performing studies with different amounts of administered drugs, the dose-dependence of tissue factors can be described and potentially guide an understanding of target interaction and saturation, key entities for suggesting an adequate dose range.
Although PBPK-modelling is developed to a high scientific level, less has been done regarding the analysis of biodistribution imaging data and extraction of the relevant parameters in relation to the plasma PBPK model. This includes e.g. how the extracellular concentration is derived from a whole tissue concentration, how the saturation of internalization is described in individual organs and finally how an optimal imaging study is designed with respect to measurement times and doses with the significant restrictions on number of examinations set by practicalities and radiation exposure.

Will detection of oxygen radicals in real time by bioimaging be a useful tool in preclinical and clinical studies of ROS reducing candidate drugs??

Glucox Biotech AB activity focuses on developing drug like compounds, targeting specific sources of reactive oxygen that causes oxidative stress in diabetes with its complications, including stroke and heart infarction, on the basis of reactive oxygen species (ROS) produces by NAD(P)H-oxidase (Nox).

Several probes have been developed for the detection of ROS in biological tissue (e.g. DHE, ROS Brite 700, H2DCF, CLA, HPF, APF, APC), some of which have been shown to work well in in vivo bioimaging. However, due to the limited ability of fluorescence to penetrate the tissue these probes have been mainly used in very small animals or for detection of ROS in skin. Nevertheless, in a recent report (Wafi et al, 2012) DHE was used to follow ROS development after LPS injection in mouse brain.

An approach that appears promising is the use of paramagnetic resonance in the detection of oxygen radicals in vivo (Ikebata et al, 2009; Beziere et al, 2012). It would be of great value to use imaging methods to detect the changes in ROS levels in situ during treatment with drug candidates aimed at reducing oxidative stress in e.g. brain, heart and pancreas, both in preclinical and clinical settings. Further more, such a method could be used for the identification of patient subpopulations genetically prone to increased sensitivity to reactive oxygen species and the development of screening procedures for identification of patients particularly benefitting from ROS inhibition.

What will be the key player for molecular imaging for early cancer diagnosis in the future – quantitative or qualitative imaging?

Everybody knows that early diagnosis of cancer save many lives and molecular imaging is one of the most important players toward this vision. Should companies and scientists that are active in this field focus on generating higher quality of images or should they focus on generating images with improved quantitative values?

Which tracer can be considered the best for a Phase 0 Trials in cancer patients and what are the pros and cons of the PET/SPECT tracers available? Can one be singeled out as an optimal choice for respective imaging method?

Which are the possible bioimaging techniques to investigate in vivo distribution of protein based drugs? Pros and cons with the different techniques when it comes to e.g. resolution, quantification, robustness and availability? How can the proteins be visualized with the different techniques?

n.a.

Cryo-electron microscopy images of liposomes. The task is to detect the circular/elliptical liposomes in the images. The images are noisy and liposomes may overlap, how can this problem be solved?

see attachment