68Ga-labeled dopamine transmitter analogues for the visualization of neurodegenerative diseases

• Applicants: Dr. Markus Piel; Professor Dr. Frank Rösch
• Subject Area: Pharmacy ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 274451541

Radiolabelled neurotransmitter analogues (NTA) for positron emission tomography (PET) require a high selective enrichment at the biological target with a low background association. This imposes strict requirements on the NTAs, specifically in terms of the receptor affinity and selectivity. Furthermore, in order to reach the targets within the brain the NTAs must have a suitable lipohilicity and metabolism. It is also required that the radiolabeled NTAs be synthesized with high radiochemical yields and high specific activities, as well as a synthesis can be carried out simply and quickly. To meet these requirements the vast majority of brain PET ligands feature a non-metallic radionuclide (i.e. 11C and 18F). However, these radionuclides are limiting due to the fact that a nearby cyclotron is required for their application - this has implications in terms of cost and convenience. 68Ga is a generator produced radionuclide, and has properties not very dissimilar to those of 18F. In addition to its excellent radiochemical properties, the particular advantage of 68Ga is its generator production, which not only ensures a long usability but also a permanent supply of 68Ga. A large number of 68Ga-radiolabelled vectors have been described in literature, in particular for the visualization of tumors. However, there are no examples of a 68Ga PET tracer for neurodegenerative disorders. Following from the principle of generator produced radionuclides the ideal scenario is one in which 68Ga-labeled NTA would be available in any nuclear medicine facility, almost instantaneously as a kit analogous to the highly successful 99mTc KIT. In this context such analogous could make an important contribution to the socially extremely relevant early diagnosis of neurodegenerative diseases such as Parkinson's disease and Alzheimer's. Generally the radiolabeling of a vector for metallo-radionuclides requires a chelator which stabilizes the radionuclides and provides a point of attachment to the vector moiety. Strict requirements are placed on the chelator relating to stability and bio-distribution of the formed complex, as well as its influence on vector-receptor binding affinity. The intention is to investigate and screen various, carefully selected chelators which show promise, for their suitability for the visualization of neurological processes. In terms of the pharmacophores (vectors) different radiopharmaceuticals for the dopaminergic system have been selected as model compounds - all of which display excellent in vivo characteristics. After completion of the extensive synthetic work and the optimization of the radiolabeling, the chelator-pharmacophore conjugates will be subjected to an extensive in vitro evaluation, to find promising candidates for further in vivo studies. In these final in vivo studies the radiolabelled pharmacophores will be investigated in terms of brain uptake, tracer kinetics, metabolism and selectivity and reversibility of binding.

• DFG Programme: Research Grants