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Development of New PET tracers for in vivo 5-HT2A and 5-HT7 Brain Imaging

Final Report Summary - 5-HT RADIOTRACERS (Development of New PET tracers for in vivo 5-HT2A and 5-HT7 Brain Imaging)

Executive Summary:

The serotonin 7 receptor subtype (5-HT7) is expressed throughout the central nervous system (CNS). A large body of literature suggests that dysfunction of 5-HT7 receptors in the CNS may be related or contribute to several brain-related disorders. However, direct links between these diseases and 5-HT7 receptor abnormalities have been difficult to elucidate due to the lack of a method for determining 5-HT7 receptor concentration in vivo.

Positron emission tomography (PET) is a non-invasive tool to characterize receptors/enzymes or other targets in vivo. For example, it can be used to quantify the number of available receptors or the concentration of drug binding to a specific target, providing receptor occupancy measurements. For drug discovery processes or disease diagnosis, these outcomes are extremely useful to inform development or treatment decisions. Thus, we believe that the development of a 5-HT7 PET radiotracer could significantly advance our understanding of neurological disorders that are affected by serotonin and may prove useful in monitoring therapy for patients with depression, schizophrenia and drug addiction.

During this Marie Curie fellowship, the main objective was to develop such a tool and validate it in vivo. Therefore, four chemical diverse 5-HT7 lead structures (oxindoles, phenethylamimes, benzolsulfonamides and 1-arylpiperazines) were identified and structurally modified in regards to PET imaging. Especially of importance were the selectivity towards the target, the lipophilicity and a simple labeling procedure. These pre-requests narrowed down the possible number of 70 to 9 PET tracers. Afterwards, we labeled and in vivo evaluated them.

[11C]Cimbi-717, an oxindole derivative, displayed the most promising characteristics to be a useful PET tracer. It was successfully radiolabeled in a sufficient radiochemical yield enabling in vivo PET studies, generated high brain uptake and showed reversible tracer kinetics, which is important for quantification. The regional distribution pattern of [11C]Cimbi-717 was compatible with 5-HT7R distribution in the pig brain, as assessed independently by autoradiography and finally, it showed a dose-dependent decrease in binding after pre-treatment with the 5-HT7R specific antagonist SB-269970. Preliminary data in non-human primates also raise hope that [11C]Cimbi-717 is able to quantify the 5-HT7 system in baboons. Access to such a successful PET-radiotracer in humans could provide a more complete picture of neurological dysfunctions and potentially serve as a biomarker for diseases.

In conclusion, we believe that the main goal of this Marie Curie fellowship could be fulfilled. We developed a 5-HT7 selective PET tracer. Further studies will elucidate the potential of this tracer.