1. Background Accumulating evidence indicates that the 5-HT1A receptor is closely implicated in the pathophysiology of major neuropsychiatric disorders, including depression, pain, neuroprotection, schizophrenia, Parkinson’s disease and Alzheimer’s disease. Because of this psychopharmacological involvement of the 5-HT1A receptor, tools to image the 5-HT1A receptor in the human brain are urgently needed. Positron emission tomography (PET) is regarded as a key molecular imaging tool, allowing for the study of the function and neurochemistry of the human brain. Until now, the development of 5-HT1A antagonist PET ligands has achieved great success. However, compared to the extensive research interests in 5-HT1A antagonist PET ligands, the development of 5-HT1A agonist PET ligands has been much less explored, and only a few examples have been reported. Thus, further exploration of even more highly potent 5-HT1A agonist PET ligands with high affinity and selectivity is therefore still a significant goal in the field. 2. Methods Numerous reports in the literature revealed that introducing a more lipophilic group at the C11 position of the aporphine structure affords analogs with high affinity and selectivity for the 5-HT1A receptor. Therefore, a series of aporphines with fluorinated alkyl or benzyl groups attached to C11 through an oxygen-linkage were synthesized and evaluated for their neuropharmacological properties. 3. Results These novel fluorinated aporphines exhibited potent and selective affinity for 5-HT1A receptor but moderate or low affinity for other brain receptors and transporter. Among them, MCL-587 displayed high affinity at the 5-HT1A receptor with an inhibitory constant (Ki) value of 21 nM. Meanwhile, the lowest Ki value for other brain receptors and transporter was about 8-fold higher than that for the 5-HT1A receptor. 4. Conclusions According to these highly promising results, such novel fluorinated aporphines could potentially prove to be valuable as 5-HT1A agonist PET ligands for detecting disease processes or therapeutic effects involving the 5-HT1A receptor. Results will be presented in detail.

Fluorinated (R)-(-)-aporphines as potential agonist positron emission tomography ligands for serotonergic 5-HT1A receptor

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.