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Iodonium ylide-mediated radiofluorination of 18F-FPEB and validation for human use.

ABSTRACT: Translation of new methodologies for labeling nonactivated aromatic molecules with (18)F remains a challenge. Here, we report a one-step, regioselective, metal-free (18)F-labeling method that uses a hypervalent iodonium(III) ylide precursor, to prepare the radiopharmaceutical (18)F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ((18)F-FPEB).Automated radiosynthesis of (18)F-FPEB was achieved by reaction of the ylide precursor (4 mg) with (18)F-Et4NF in dimethylformamide at 80°C for 5 min and formulated for injection within 1 h.(18)F-FPEB was synthesized in 20% ± 5% (n = 3) uncorrected radiochemical yields relative to (18)F-fluoride, with specific activities of 666 ± 51.8 GBq (18 ± 1.4 Ci)/?mol at the end of synthesis and was validated for human use.Radiofluorination of iodonium (III) ylides proved to be an efficient radiosynthetic strategy for synthesis of (18)F-labeled radiopharmaceuticals.

SUBMITTER: Stephenson NA

PROVIDER: S-EPMC4878451 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Iodonium ylide-mediated radiofluorination of 18F-FPEB and validation for human use.

Stephenson Nickeisha A NA Holland Jason P JP Kassenbrock Alina A Yokell Daniel L DL Livni Eli E Liang Steven H SH Vasdev Neil N

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20150205 3

<h4>Unlabelled</h4>Translation of new methodologies for labeling nonactivated aromatic molecules with (18)F remains a challenge. Here, we report a one-step, regioselective, metal-free (18)F-labeling method that uses a hypervalent iodonium(III) ylide precursor, to prepare the radiopharmaceutical (18)F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ((18)F-FPEB).<h4>Methods</h4>Automated radiosynthesis of (18)F-FPEB was achieved by reaction of the ylide precursor (4 mg) with (18)F-Et4NF in dimethyl ...[more]

PMID: 25655630

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Project description:As a member of cyclic nucleotide phosphodiesterase (PDE) enzyme family, PDE10A is in charge of the degradation of cyclic adenosine (cAMP) and guanosine monophosphates (cGMP). While PDE10A is primarily expressed in the medium spiny neurons of the striatum, it has been implicated in a variety of neurological disorders. Indeed, inhibition of PDE10A has proven to be of potential use for the treatment of central nervous system (CNS) pathologies caused by dysfunction of the basal ganglia–of which the striatum constitutes the largest component. A PDE10A-targeted positron emission tomography (PET) radioligand would enable a better assessment of the pathophysiologic role of PDE10A, as well as confirm the relationship between target occupancy and administrated dose of a given drug candidate, thus accelerating the development of effective PDE10A inhibitors. In this study, we designed and synthesized a novel 18F-aryl PDE10A PET radioligand, codenamed [18F]P10A-1910 ([18F]9), in high radiochemical yield and molar activity via spirocyclic iodonium ylide-mediated radiofluorination. [18F]9 possessed good in vitro binding affinity (IC50 = 2.1 nmol/L) and selectivity towards PDE10A. Further, [18F]9 exhibited reasonable lipophilicity (logD = 3.50) and brain permeability (Papp > 10 × 10−6 cm/s in MDCK-MDR1 cells). PET imaging studies of [18F]9 revealed high striatal uptake and excellent in vivo specificity with reversible tracer kinetics. Preclinical studies in rodents revealed an improved plasma and brain stability of [18F]9 when compared to the current reference standard for PDE10A-targeted PET, [18F]MNI659. Further, dose–response experiments with a series of escalating doses of PDE10A inhibitor 1 in rhesus monkey brains confirmed the utility of [18F]9 for evaluating target occupancy in vivo in higher species. In conclusion, our results indicated that [18F]9 is a promising PDE10A PET radioligand for clinical translation. Graphical abstract A novel positron emission tomography (PET) ligand [18F]P10A-1910 realized PDE10A quantitative visualization and target engagement in vivo.Image 1

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Iodonium ylide-mediated radiofluorination of 18F-FPEB and validation for human use.

Publications

Iodonium ylide-mediated radiofluorination of 18F-FPEB and validation for human use.

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