Project Details
Projekt
New PET radioligands for imaging of cannabinoid CB2 receptors
Subject Area
Pharmacy
Term
from 2010 to 2014
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 189588932
Molecular imaging of the components of the cannabinoid system has the potential to support research on the mechanisms of various central nervous system (CNS) and cancerous diseases and the development of new therapies. The current evidence-based knowledge of cannabinoids as antitumor and palliative as well as neuroprotective and antiinflammatory agents identifies in particular cannabinoid receptor type 2 (CB2) as most crucial regarding the transmission of these specific non-psychotic effects. However, the applicability of CB2 specific ligands for molecular imaging by means of positron emission tomography (PET) is still restricted due to shortcomings of the available small molecules during the translation from in vitro to in vivo situation. Therefore, combining the proven expertise of three research groups in pharmaceutical, medicinal and radiochemistry as well as in the successful transfer of PET radioligands from preclinical studies up to clinically suitable PET radiotracers, this joint project aims to the design, synthesis and thorough evaluation of novel radiolabelled CB2 ligands. As the identification, development, and evaluation of suitable molecules targeting this particular receptor in brain is scientifically challenging with respect to brain uptake, metabolic stability, and target specificity, synthetic as well as computational approaches covering ligand design, receptor modelling, and ADME parameters will be utilized. By focusing on N-arylpropionamides, quinolinecarboxamides and indolyl-oxoacetamides amenable to 18F- as well as 11C-labelling we will identify the most suitable compounds, subsequently to be validated preclinically in suitable animal models such as mouse model of neuroinflammation and pig model of traumatic brain injury. The main objectives of the project are- Synthesis of novel CB2 ligands with high CB2 receptor affinity, high selectivity over the CB1 receptor, appropriate pharmacokinetic properties and high permeability into the central nervous system.- Synthesis of appropriate precursors, which allow the introduction of positron emitting isotopes 18F and 11C into the most promising CB2 ligands.- Establishment of reproducible radiosynthetic procedures allowing the preparation of PET tracers with high radiochemical yields, radiochemical purities and specific radioactivities. The radiochemical procedures will be transferred between the cooperating partners.- Careful biological evaluation in vitro and in different animal models. - Elaboration of automated procedure(s) for the best selected compound(s) which will be applied to obtain reproducible yields of radiotracers in higher levels of radioactivity.
DFG Programme
Research Grants
