Funding Agency: Ministerio de Economía, Industria y Competitividad.
Innovative 18F-, 11C- and 13N- radiochemistry: Ion-induced isotopic exchange, Negishi cross-coupling and enzymatic reactions to expand the portfolio of PET tracers.
In this project, innovative radiolabelling strategies for the preparation of radiotracers labelled with the most commonly used positron emitters that can be routinely produced in biomedical cyclotrons (18F, 11C, and 13N) will be developed.
For fluorine-18, the aim of the project is to further exploit the radically innovative ion-induced isotopic exchange reaction recently developed by our research group, which has been applied to the preparation of the radiofluorinated gases [18F]SF6 and [18F]CF4, and proof the efficacy of these gases as regional ventilation markers in an animal model of impaired lung ventilation. Additionally, technological aspects for the storage, formulation, dosing, and transport of the labelled gases, which should facilitate future translation into the clinical setting, will be developed.
For Carbon-11, the project will tackle the development of a general method for the formation of 11C-C bonds on aryl halides starting from the labelled precursor [11C]CH3I via Negishi cross-coupling reaction. The new methodology will be applied to the preparation of biologically active compounds (transthyretin stabilizers), and their pharmacokinetic properties will be evaluated in rodents.
For Nitrogen-13, the preparation of 13N-labelled amino acids using enzymatic methods will be explored. Soluble multi-enzyme systems will be first developed. The immobilization of the enzymes using different solid supports will be investigated in order to implement continuous flow processes and full automation of the synthetic procedures. Finally, selected amino acids will be investigated as metabolic markers in xenograft and genetic mouse models of prostate cancer.
The radiochemical methods developed and the knowledge gained through the project will enable the preparation of a wide range of radiotracers which were inaccessible to date, some of them with unprecedented applications in the context of PET imaging. Hence, execution of the project may have a significant scientific and socio-economical impact, the latter by increasing the competitiveness of the (radio)pharmaceutical and technological industries, and by providing efficient tools for a better and more efficient diagnostic and monitoring of the response to treatment.
Funding Agency: Basque Government
Imaging biomarkers for early diagnosis, predicting cognitive decline and monitoring the progression of Alzheimer's disease: a translational approach
Dementia is defined as a chronic and global deterioration of the higher functions, acquired and without alteration of the level of consciousness that is characterized by alteration of the memory and associates cognitive alterations and of the executive functions, the most common being Alzheimer's disease (AD). AD is characterized by extracellular amyloid deposition, the appearance of hyperphosphorylated Tau protein, synaptic dysfunction, and neuroinflammation.
The diagnosis of AD is fundamentally clinical, which makes it difficult to establish a diagnosis in the early stages of the disease. The most recent trends propose establishing a definition of AD based on the evaluation of biomarkers, known as the AT(N) scheme, which establishes three groups of biomarkers: amyloid plaques (A), fibrillary tau protein (T) and neurodegeneration or neuronal damage (N). The biomarkers of β-amyloid plaques and neurodegeneration can be determined by positron emission tomography (PET), however, there is no registered radiopharmaceutical specialty in clinical practice for the detection of p-Tau.
The present project aims to evaluate the ability of two radiotracers, [18F]LR-01 and [11C]BChE-01, to determine the presence of hyperphosphorylated p-Tau and over-expression of the enzyme butyrylcholinesterase (associated with the pathological course of AD and used as a therapeutic target in clinical trials) respectively.
Longitudinal studies in animal models of AD are proposed to correlate the temporal evolution of the pathology with the specific brain capture of both radiotracers. In addition, other phenomena will be investigated such as the presence of deposits of β-amyloid and brain inflammation with clinically validated tracers.
In parallel, histological, immunohistochemical and autoradiography studies will be carried out on brains in order to validate the results in vivo. Finally, the properties of the new radiotracers will be investigated in post-mortem tissue from patients with a histological diagnosis of AD, in order to determine their capacity for the selective detection of p-Tau ([18F]LR-01) and butyrylcholinesterase ([11C]BChE-01) in human tissue.
The development of the tracers will facilitate their implementation in the clinical environment and will be a fundamental tool for the early/differential diagnosis of AD, the prediction of cognitive impairment and the evaluation of the therapeutic efficacy of new treatments or drugs.
To tackle this project, a multidisciplinary team with a clear translational vision is proposed, bringing together experience in different areas of knowledge. The research team is made up of professionals with extensive experience in research and innovation (CIC biomaGUNE), in histopathological diagnosis in neurodegenerative diseases (OSI Araba Pathological Anatomy Service), functional neuroimaging by Positron Emission Tomography (PET) and clinical experience (OSI Araba Nuclear Medicine Service), as well as teaching professionals from the Faculty of Medicine of the University of the Basque Country (UPV/EHU).
The coordinator of the project, Dr. Llop, has more than 15 years of experience in the field of radiochemistry and nuclear imaging, both at a preclinical and clinical level.
Dr. Gómez-Vallejo is responsible for the Radiochemistry Platform and coordinates all the studies carried out at the facility in the context of radiochemistry and nuclear imaging.
Dr. Pedro Ramos-Cabrer is a specialist in magnetic resonance imaging and functional imaging techniques applied to animal models of pathologies.
Dr. Unai Cossío is responsible for the Radioimaging and Image Analysis Platform of CIC biomaGUNE.
Dr. I. Tobalina Larrea is Head of the Nuclear Medicine Service at the University Hospital of Alava.
Dr Rebeca Ruiz Onandi is coordinator of the Neurological Tissue Bank of the Basque Biobank at the University Hospital Node in Araba/Bioaraba.
Dr Isabel Guerra Merino directs the Clinical Management Unit of Pathological Anatomy of the OSI ARABA and is Coordinator of the Basque Biobank in Alava.