Advancing PET imaging of central 5-HT2a receptors with [18F]MDL100907: Passing the stumbling blocks in late-stage Ni-mediated [18F]fluorination

554 Objectives Non-invasive brain imaging with PET is not routinely used in clinical practice. A primary explanation is that effective biomarkers for mental illness are often not available. When available, radiotracers that may be used as biomarkers are not optimized. The serotonin 2a receptor (5HT2a) is implicated in the pathophysiology of many neuropsychiatric disorders. Although PET ligands exist for imaging 5HT2a in humans, there is a continued effort to improve these agents with a particular focus on the development of F18 labeled radiotracers. The benchmark by which these new radiotracers for 5HT2a compared is the C11 labeled MDL100,907. Thus, direct F18 labeling of MDL100,907 is our major goal which has been extremely challenging with conventional F18 labeling methods. Methods We describe an innovative approach to labeling [18F] MDL100907 using a late-stage Ni-mediated oxidative reaction, which is the only method that we know of that can operate at room temperature in the presence of water and lead to high specific activity F18 labeling. We have found the Ni mediated fluorination chemistry was best performed in buffered conditions, which opens a new door for applying modern F18 chemistry to PET imaging. Results The highly selective yet conventionally inaccessible 5-HT2a antagonist, [18F]MDL100907 was synthesized using Ni-mediated late-stage [18F]fluorination in Siemens GN automated synthesizer. The [18F]MDL 100907 was then compared with [11C]MDL100907 for PET imaging 5-HT2a receptors in the same baboon on the same day. The regional distribution of [18F]MDL100907 is in great accordance with the known distribution of [11C]MDL100907. Conclusions Given the longer half-life (110 minute) and higher resolution of fluorine-18, [18F]MDL100907 would be more valuable to the neuroscience community for imaging central 5-HT2a receptors and studying brain-related disorders. Human PET imaging with [18F]MDL100907 is in progress.