Synthesis and Imaging Validation of [¹⁸F]MDL100907 Enabled by Ni-Mediated Fluorination

Abstract

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.

Applications of Fluorine in Medicinal Chemistry

“…158 A translational application of this chemistry is exemplified by the synthesis of [ 18 F]-MDL-100907 (300, volinanserin), a promising new PET radioligand for labeling the 5HT 2a receptor, from 297 through the intermediacy of 298 which is used to alkylate the piperidine 299 (Scheme 9). 160 (d) Synthetic Methods for the [ 18 F]-Labeling of Biologics. The increase in the application of biologics-based drugs has stimulated considerable interest in methods for the introduction of 18 F into these molecules with a focus on the use of chemical reactions that are bioorthogonal in nature.…”

Development of a Fluorinated Class-I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance

“…The currently available version of Martinostat is labelled with carbon-11, which limits its practicality, since logistics are constrained by its 20 min half-life 17, 18 . One key achievement presented in this work is the development of an [ 18 F]-HDAC-radiotracer, which enables in vivo quantification of HDAC with the benefits of a longer half-life.…”

Late-stage [18F]fluorination: new solutions to old problems

“…6d To address these limitations, Hooker and Ritter followed up this work with a method for [ 18 F]fluorination of arylnickel complexes 11 (Scheme 3a) that offers a one-step, rapid oxidative fluorination of a range of arenes using aqueous [ 18 F]fluoride and oxidant 12 . 7 Despite the relatively wide substrate scope of this reaction, Hooker and Ritter noted two key limitations in this method: (1) increasing the volume of aq. [ 18 F]fluoride to the Ni-mediated reaction (>1% v/v) degraded the Ni complex and oxidant and (2) classical azeotropic drying of the [ 18 F]fluoride resulted in solutions that were too basic and thus resulted in low RCY.…”

“…7b Elution of the [ 18 F]fluoride from the ion exchange cartridge with tetrabutylammonium bicarbonate (TBAB) (to produce [ 18 F]TBAF) was adventitious, as was the addition of pyridinium p-toluenesulfonate (PPTS) to produce a bicarbonate buffer that was compatible with oxidant 12 . In a pre-clinical application of the chemistry, [ 18 F]MDL100907 16 , a radiotracer for the 5HT 2a receptor, was synthesized and evaluated in non-human primates.…”