Novel ¹⁸F-Labeled κ-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of ¹⁸F-LY2459989 in Nonhuman Primates

Abstract

The κ-opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation ofF-LY2459989 as the first F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison withC-LY2459989. The novel radioligandF-LY2459989 was synthesized by F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time-activity curves and the calculation of binding parameters. With the iodonium ylide precursor, F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (>99%), and mean molar activity (1,175 GBq/μmol; = 6). In monkeys,F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of F-LY2459989 in vivo. Regional time-activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex> insula > caudate/putamen > frontal cortex > temporal cortex > thalamus, consistent with the reported KOR distribution in the monkey brain. The evaluation ofF-LY2459989 in nonhuman primates demonstrated many attractive imaging properties: fast tissue kinetics, specific and selective binding to the KOR, and high specific binding signals. A side-by-side comparison of F-LY2459989 andC-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo.

Chemie der Positronenemissionstomographie: Aktuelle Fortschritte bei 11C‐, 18F‐, 13N‐ und 15O‐Markierungsreaktionen

“…Da die Radiofluorierung von Aryliodoniumyliden eine effiziente und metallfreie Methode für nicht‐aktivierte Arene ist, konnte auf diesem Wege eine Vielzahl von klinisch relevanten Radiopharmazeutika und 18 F‐markierten Wirkstoffgerüste hergestellt werden (Schema ) . Anzumerken ist, dass die [ 18 F]FPEB‐Synthese mittels SCIDY‐Technologie vollständig automatisiert werden konnte, was eine erhebliche Verbesserung (3‐ bis 10‐fach) der RCY und der molaren Aktivität im Vergleich zur klassischen S N Ar‐Methode ermöglichte.…”

Chemistry for Positron Emission Tomography: Recent Advances in 11C‐, 18F‐, 13N‐, and 15O‐Labeling Reactions

“…[81,132,133,[135][136][137][138][139][140][141][142][143] It is noteworthy that [ 18 F]FPEB synthesized by the SCIDYm ethod was fully automated, thereby resulting in asubstantial improvement (3-10 fold) in the RCY and molar activity compared with the traditional S N Ar method. [81,132,133,[135][136][137][138][139][140][141][142][143] It is noteworthy that [ 18 F]FPEB synthesized by the SCIDYm ethod was fully automated, thereby resulting in asubstantial improvement (3-10 fold) in the RCY and molar activity compared with the traditional S N Ar method.…”

Quantitative Rodent Brain Receptor Imaging

“…GLU tracers have shown reduced availability of the type 1 metabotropic GLU receptor (mGluR1) in patients with hereditary and sporadic cerebellar ataxia, which now is proposed as a specific imaging biomarker of the disease [234]. A tracer targeting the κ-opioid receptor was evaluated in non-human primates for the first time, potentially providing a novel tool to investigate this system in humans [235]. Another example is the 18-kDa translocator protein (TSPO) tracer, which has been used to provide preliminary imaging data on neuroinflammation in non-human primates [236] and in patients [237,238].…”