Synthesis and imaging validation of [¹⁸F]MDL100907 enabled by Ni-mediated fluorination.
Several voids exist in reliable positron emission tomography (PET) radioligands for quantification of the serotonin (5HT) receptor system. Even in cases where 5HT radiotracers exist, challenges remain that have limited the utility of 5HT imaging in clinical research. Herein we address an unmet need in 5HT2a imaging using innovative chemistry. We report a scalable and robust synthesis of [(18)F]MDL100907, which was enabled by a Ni-mediated oxidative fluorination using [(18)F]fluoride. This first demonstration of a Ni-mediated fluorination used for PET imaging required development of a new reaction strategy that ultimately provided high specific activity [(18)F]MDL100907. Using the new synthetic strategy and optimized procedure, [(18)F]MDL100907 was evaluated against [(11)C]MDL100907 for reliability to quantify 5HT₂a in the nonhuman primate brain and was found to be superior based on a single scan analysis using the same nonhuman primate. The use of this new 5HT₂a radiotracer will afford clinical neuroscience research the ability to distinguish 5HT₂a receptor abnormalities binding between healthy subjects and patients even when group differences are small.
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, 13th Street, Charlestown, Massachusetts 02129, United States.
Hong
H
Ren
Hsiao-Ying
HY
Wey
Martin
M
Strebl
Ramesh
R
Neelamegam
Tobias
T
Ritter
Jacob M
JM
Hooker
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D005464:Fluorobenzenes / Q000138:chemical synthesis / Q000493:pharmacokinetics; D054879:Halogenation; D008279:Magnetic Resonance Imaging; D048530:Papio anubis; D010880:Piperidines / Q000138:chemical synthesis / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013997:Time Factors
D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D005464:Fluorobenzenes; D010880:Piperidines; D019275:Radiopharmaceuticals; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; C079049:volinanserin