In Silico optimization of brain imaging probes with enhanced permeation
Life and Health Sciences
Diagnostic, Therapies and Public Health
Technological advances in imaging have led to tremendous progress in medical sciences in the last few decades. Among these techniques, Magnetic Resonance Imaging (MRI) stands out as a versatile technique with outstanding spatial resolution that does not involve the use of X-rays or ionizing radiation.
However, clinical utilization of MRI often requires the use of contrast agents. Among these, paramagnetic gadolinium(III) chelates such as gadoteric acid (GdDOTA, Dotarem) are widely used. Due to their hydrophilicity, these complexes do not cross the blood-brain barrier, unless the latter is compromised. They are therefore useful in the detection of brain tumors, but cannot be used in diagnosis of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
It is believed that one of the main reasons for this failure is that intermediate evaluations in model studies, which would allow a more quantitative characterization - e.g., in terms of energy barriers or permeation rates - have not yet been carried out.
This project will solve this problem by starting at the most fundamental level: molecular simulation at the atomic or quasi-atomic scales. In silico methodologies based on molecular dynamics simulations will be carried out to calculate permeability coefficients, which will allow a first rank of possible GdL candidates (L denotes a DOTA-based ligand, with structural modifications aiming at enhancing membrane permeation), for subsequent synthesis and experimental testing.
Contacts:
Luís Loura
email: lloura@ff.uc.pt
Coimbra Chemistry Center, Faculty of Pharmacy
