Preparation of the metabotropic glutamate receptor 5 (mGluR5) PET tracer [ 18 F]FPEB for human use: An automated radiosynthesis and a novel one-pot synthesis of its radiolabeling precursor

Lim, Keunpoong; Labaree, David; Li, Songye; Huang, Yiyun

doi:10.1016/j.apradiso.2014.09.006

Cited by 24 publications

(20 citation statements)

References 11 publications

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“…Harsh conditions, including high temperatures and prolonged reaction times are generally required and several chemical and radiochemical impurities are usually generated during these reactions, thereby complicating purification. The original radiosynthesis of 18 F-FPEB used a chlorinated precursor (Scheme 2, entry I) (14). We and other laboratories (9, 14, 15) have validated a reproducible radiosynthesis of 18 F-FPEB via 3-nitro-5-(pyridin-2-ylethynyl)benzonitrile (Scheme 2, entry II) which resulted in 1 – 5 % radiochemical yield for clinical research studies.…”

Section: Discussionmentioning

confidence: 99%

“…The original radiosynthesis of 18 F-FPEB used a chlorinated precursor (Scheme 2, entry I) (14). We and other laboratories (9, 14, 15) have validated a reproducible radiosynthesis of 18 F-FPEB via 3-nitro-5-(pyridin-2-ylethynyl)benzonitrile (Scheme 2, entry II) which resulted in 1 – 5 % radiochemical yield for clinical research studies. Notably, our efforts to further optimize the radiochemical yield of 18 F-FPEB by use of the nitro-precursor in the presence of reduced base concentrations still required high temperatures to proceed (ca.…”

Section: Discussionmentioning

confidence: 99%

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Iodonium Ylide–Mediated Radiofluorination of ¹⁸F-FPEB and Validation for Human Use

et al. 2015

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Translation of new methodologies for labeling non-activated aromatic molecules with fluorine-18 remains a challenge. Here, we report a one-step, regioselective, metal-free 18F-labeling method that employs a hypervalent iodonium(III) ylide precursor, to prepare the radiopharmaceutical 18F-FPEB. Methods Automated radiosynthesis of 18F-FPEB was achieved by reaction of the ylide precursor (4 mg) with 18F-NEt4F in DMF at 80 °C for 5 minutes, and formulated for injection within 1 hour. Results 18F-FPEB was synthesized in 15 – 25% (n = 3) uncorrected radiochemical yields relative to 18F-fluoride, with specific activities of 666 ± 51.8 GBq/μmol (18 ± 1.4 Ci/μmol) at the end-of-synthesis (EOS). The radiopharmaceutical was validated for human use. Conclusions Radiofluorination of iodonium (III) ylides proved to be an efficient radiosynthetic strategy for synthesis of 18F-labeled radiopharmaceuticals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Iodonium Ylide–Mediated Radiofluorination of ¹⁸F-FPEB and Validation for Human Use

et al. 2015

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“…[ 18 F]FPEB was synthesized using a previously published method [13]. Average specific activity was 195 ± 47 MBq/nmol (n = 14) at the end of synthesis.…”

Section: Methodsmentioning

confidence: 99%

Test–retest reproducibility of the metabotropic glutamate receptor 5 ligand [18F]FPEB with bolus plus constant infusion in humans

Park

Sullivan

Planeta

et al. 2015

Eur J Nucl Med Mol Imaging

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Purpose [18F]FPEB is a promising PET radioligand for the metabotropic glutamate receptor 5 (mGluR5), a potential target for the treatment of neuropsychiatric diseases. The purpose of this study was to evaluate the test-retest reproducibility of [18F]FPEB in the human brain. Methods Seven healthy male subjects were scanned twice, 3–11 weeks apart. Dynamic data were acquired using bolus plus infusion of 162±32 MBq [18F]FPEB. Four methods were used to estimate volume of distribution (VT): equilibrium analysis (EQ) using arterial (EQA) or venous input data (EQV), MA1, and two-tissue compartment model (2T). Binding potential (BPND) was also estimated using cerebellar white matter (CWM) or grey matter (CGM) as a reference region using EQ, 2T and MA1. Absolute test-retest variability (aTRV) of VT and BPND were calculated for each method. Venous blood measurements (CV) were compared with arterial input (CA) to examine their usability for EQ analysis. Results Regional VT estimated by the four methods displayed a high degree of agreement (r2 ranging from 0.83 to 0.99 between methods), although EQA and EQV overestimated VT by a mean of 9% and 7%, respectively, compared to 2T. Mean aTRV of VT were 11% by EQA, 12% by EQV, 14% by MA1 and 14% by 2T. Regional BPND also agreed well between methods and mean aTRV of BPND was 8–12% (CWM) and 7–9% (CGM). Venous and arterial blood concentrations of [18F]FPEB were well matched during equilibrium (CV=1.01·CA, r2=0.95). Conclusion [18F]FPEB binding shows good test-retest variability with minor differences between analysis methods. Venous blood can be used as an alternative for input function measurement instead of arterial blood in EQ analysis. Thus, [18F]FPEB is an excellent PET imaging tracer for mGluR5 in humans.

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“…18 F-fluoride was then eluted from the cartridge into the reactor with a 1.0-to 1.4-mL solution of Kryptofix-222 (10 mg) and K 2 CO 3 (1-2 mg) in acetonitrile/ water (1:0.4, v/v). Preparation of the anhydrous 18 F-fluoride-Kryptofix-222 complex by azeotropic distillation with acetonitrile followed the procedure previously reported (15). After the reactor was cooled to 60°C, 1.5 mg of the precursor in 0.5 mL of anhydrous N,N-dimethylformamide (DMF) were added and the mixture heated at 110°C for 30 min.…”

Section: Radiosynthesis Of 18 F-pf-05270430mentioning

confidence: 99%

Preclinical Evaluation of ¹⁸F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme

et al. 2016

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The enzyme phosphodiesterase 2A (PF-05270430) is a potential target for development of novel therapeutic agents for the treatment of cognitive impairments. The goal of the present study was to evaluate the PDE2A ligand 18 F-PF-05270430, 4-(3-fluoroazetidin- ,2,4]triazine, in nonhuman primates. Methods: 18 F-PF-05270430 was radiolabeled by 2 methods via nucleophilic substitution of its tosylate precursor. Tissue metabolite analysis in rodents and PET imaging in nonhuman primates under baseline and blocking conditions were performed to determine the pharmacokinetic and binding characteristics of the new radioligand. Various kinetic modeling approaches were assessed to select the optimal method for analysis of imaging data. Results: 18 F-PF-05270430 was synthesized in greater than 98% radiochemical purity and high specific activity. In the nonhuman primate brain, uptake of 18 F-PF-05270430 was fast, with peak concentration (SUVs of 1.5-1.8 in rhesus monkeys) achieved within 7 min after injection. The rank order of uptake was striatum . neocortical regions . cerebellum. Regional time-activity curves were well fitted by the 2-tissuecompartment model and the multilinear analysis-1 (MA1) method to arrive at reliable estimates of regional distribution volume (V T ) and binding potential (BP ND ) with 120 min of scan data. Regional V T values (MA1) ranged from 1.28 mL/cm 3 in the cerebellum to 3.71 mL/cm 3 in the putamen, with a BP ND of 0.25 in the temporal cortex and 1.92 in the putamen. Regional BP ND values estimated by the simplified reference tissue model (SRTM) were similar to those from MA1. Test-retest variability in high-binding regions (striatum) was 4% ± 6% for MA1 V T , 13% ± 6% for MA1 BP ND , and 13% ± 7% SRTM BP ND , respectively. Pretreatment of animals with the PDE2A inhibitor PF-05180999 resulted in a dose-dependent reduction of 18 F-PF-05270430 specific binding, with a half maximal effective concentration of 69.4 ng/mL in plasma PF-05180999 concentration. Conclusion: 18 F-PF-05270430 displayed fast and reversible kinetics in nonhuman primates, as well as specific binding blockable by a PDE2A inhibitor. This is the first PET tracer with desirable imaging properties and demonstrated ability to image and quantify PDE2A in vivo.

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Preparation of the metabotropic glutamate receptor 5 (mGluR5) PET tracer [ 18 F]FPEB for human use: An automated radiosynthesis and a novel one-pot synthesis of its radiolabeling precursor

Cited by 24 publications

References 11 publications

Iodonium Ylide–Mediated Radiofluorination of ¹⁸F-FPEB and Validation for Human Use

Iodonium Ylide–Mediated Radiofluorination of ¹⁸F-FPEB and Validation for Human Use

Test–retest reproducibility of the metabotropic glutamate receptor 5 ligand [18F]FPEB with bolus plus constant infusion in humans

Preclinical Evaluation of ¹⁸F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme

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Preparation of the metabotropic glutamate receptor 5 (mGluR5) PET tracer [ 18 F]FPEB for human use: An automated radiosynthesis and a novel one-pot synthesis of its radiolabeling precursor

Cited by 24 publications

References 11 publications

Iodonium Ylide–Mediated Radiofluorination of 18F-FPEB and Validation for Human Use

Iodonium Ylide–Mediated Radiofluorination of 18F-FPEB and Validation for Human Use

Test–retest reproducibility of the metabotropic glutamate receptor 5 ligand [18F]FPEB with bolus plus constant infusion in humans

Preclinical Evaluation of 18F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme

Contact Info

Product

Resources

About

Iodonium Ylide–Mediated Radiofluorination of ¹⁸F-FPEB and Validation for Human Use

Iodonium Ylide–Mediated Radiofluorination of ¹⁸F-FPEB and Validation for Human Use

Preclinical Evaluation of ¹⁸F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme