Synthese, Radiosynthese und Evaluierung von selektiven Dopamintransporter-Liganden zur Untersuchung des Dopamintransporter-Status in vivo
Final Report Abstract
In conclusion, novel highly promising candidate DAT-ligands were synthesised and characterised. Among these, two compounds emerged as outstandingly selective. The novel cocaine derivative [18F]PR04.MZ provides appropriate characteristics for routine PD-diagnosis with PET. The disadvantageous, slow equilibria, as well as the non-selective binding profile that has limited the use of many of its congeners are not an issue with the new compound. This might be particularly useful for the accurate and sensitive determination of therapeutic doses for PD-medication and the raring of therapeutic success and for imaging of low density, extra-striatal DAT. Furthermore, the novel imaging agent can be used as versatile tool for the development of new pharmaceuticals which interact with the dopaminergic system in general and in particular with the reuptake of DA. The novel, microwave enhanced labelling method for the nucleophilic aliphatic fluorinarion with [18F]F' affords high labelling yields in shorter reaction times, which is beneficial for the routine production of [18F]PR04.MZ and similar compounds. In contrast, the carbon-11 labelled analogue can reliably be utilised for multi-injection studies in psychiatric and neuro-scientific research. Thereby new insights into the extra-striatal contributions to a variety of the dopaminergic system affecting pathologies might be provided. In this relationship, improved conditions for the 11 C-methylation were developed that utilise the readily available [11C]Mel, which can be produced in high specific activity. Furthermore the initial aspects towards the development of a 68Ga-labelled DAT-ligand for routine diagnostic applications were conducted. With the obtained informations in hand, the further improvement of the required lipophilic bifunctional chelator and the subsequent introduction of the chelating moiety into the tropane body are the next milestones. The Galabelled compound would possess a remarkable impact on the clinical availability of DAT-ligands for routine PD diagnosis. Thereby, a generator based low-cost altemative to 18F' fluorinated DAT-ligands would be provided for PET imaging.
