EURIPIDES · EUropean Research initiative to develop Imaging Probes for early In-vivo Diagnosis and Evaluation of response to therapeutic Substances

We aim develop in-vivo imaging biomarker of multidrug transporter function as a generic tool for the prediction, diagnosis, monitoring and prognosis of major CNS diseases, as well as to provide support and guidance for therapeutic interventions. Multidrug transporters actively transport substrates (including multiple CNS drugs) against concentration gradients across the blood-brain barrier (BBB). Overactivity of these efflux transporters results in inadequate access of CNS drugs to their targets and hampers the build up of adequate tissue levels of these drugs in the brain, greatly limiting their therapeutic efficacy. As such, this ""transporter hypothesis"" of drug resistance is applicable to a broad range of CNS drugs and patients with a variety of CNS diseases who critically depend on these drugs. Efflux transporters may also influence brain elimination of Aβ, the hallmark of Alzheimer’s disease (AD). Impaired multidrug transporter function with reduced clearance of Aβ could lead to accumulation within the extracellular space, contributing to the pathogenesis of AD. We will determine the contribution of multidrug transporters to impaired brain uptake of drugs for the prediction of therapeutic responses, or the contribution of impaired transporter function to reduced clearance of toxic substances for the early in-vivo diagnosis of AD. Circumvention of pharmacoresistance, or increasing clearance, may involve inhibitors of multidrug transporters or sophisticated alternative therapies, but demonstration of overexpression or underactivity of transporter function is an essential and necessary first step. An in-vivo imaging biomarker of multidrug transporter function is essential for identifying altered transporter activity in individual patients. If a relation between overexpression and therapy resistance, or underactivity and AD, can be demonstrated, such a biomarker will provide the means for predicting treatment response, or early diagnosis, in individual patients.""