Iodonium ylides for one-step, no-carrier-added radiofluorination of electron rich arenes, exemplified with 4-(([<sup>18</sup>F]fluorophenoxy)-phenylmethyl)piperidine NET and SERT ligands

Cardinale, Jens; Neumaier, Bernd; Humpert, Swen; Coenen, Heinz H.

doi:10.1039/c4ra00674g

Cited by 71 publications

(47 citation statements)

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“…This technology was introduced by Satyamurthy and Barrio using barbituric or Meldrum’s acid auxiliaries (6). A recent study by Coenen and coworkers demonstrated the satisfactory application of this method using Meldrum’s acid auxiliaries, but led to non-regiospecific labeling and formation of several byproducts (7). Concurrently, we explored the application of iodonium ylide precursors with barbituric acid and Meldrum’s acid auxiliaries for 18 F-labeling but also found yields to be sub-optimal (8).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…Parenthetically, novel methods reported for 18 F-labeling of substrates that are not activated for S N Ar substitutions can be adapted for [ 18 F]FIBG synthesis and efforts are under way in this direction in our laboratory. These methods include use of diaryl iodonium salts [21, 22] and iodonium ylide [23] precursors, and those mediated by nickel, palladium, and copper [24–27]. …”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

Vaidyanathan

McDougald

Koumarianou

et al. 2015

Nuclear Medicine and Biology

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Introduction Radioiodinated meta-iodobenzylguanidine (MIBG), a norepinephrine transporter (NET) substrate, has been extensively used as an imaging agent to study the pathophysiology of the heart and for the diagnosis and treatment of neuroendocrine tumors. The goal of this study was to develop an 18F-labeled analogue of MIBG that like MIBG itself could be synthesized in a single radiochemical step. Towards this end, we designed 4-fluoropropoxy-3-iodobenzylguanidine (FPOIBG). Methods Standards of FPOIBG and 4-fluoropropoxy-3-bromobenzylguanidine (FPOBBG) as well as their tosylate precursors for labeling with 18F, and a tin precursor for the preparation of radioiodinated FPOIBG were synthesized. Radiolabeled derivatives were synthesized by nucleophilic substitution and electrophilic iododestannylation from the corresponding precursors. Labeled compounds were evaluated for NET transporter recognition in in vitro assays using three NET-expressing cell lines and in biodistribution experiments in normal mice, with all studies performed in a paired-label format. Competitive inhibition of [125I]MIBG uptake by unlabeled benzylguanidine compounds was performed in UVW-NAT cell line to determine IC50 values. Results [18F]FPOIBG was synthesized from the corresponding tosylate precursor in 5.2 ± 0.5% (n = 6) overall radiochemical yields starting with aqueous fluoride in about 105 min. In a paired-label in vitro assay, the uptake of [18F]FPOIBG at 2 h was 10.2 ± 1.5%, 39.6 ± 13.4%, and 13.3 ± 2.5%, in NET-expressing SK-N-SH, UVW-NAT, and SK-N-BE(2c) cells, respectively, while these values for [125I]MIBG were 57.3 ± 8.1%, 82.7 ± 8.9%, and 66.3 ± 3.6%. The specificity of uptake of both tracers was demonstrated by blocking with desipramine. The 125I-labeled congener of FPOIBG gave similar results. On the other hand, [18F]FPOBBG, a compound recently reported in the literature, demonstrated much higher uptake, albeit less than that of co-incubated [125I]MIBG. IC50 values for FPOIBG were higher than that obtained for MIBG and FPOBBG. Unlike the case with [18F]FPOBBG, the heart uptake [18F]FPOIBG in normal mice was significantly lower than that of MIBG. Conclusion Although [18F]FPOIBG does not appear to warrant further consideration as an 18F-labeled MIBG analogue, analogues wherein the iodine in it is replaced with a chlorine, fluorine or hydrogen might be worth pursuing. Advances in knowledge and implications for patient care An 18F-labeled analogue of the well-known radiopharmaceutical MIBG could have significant impact, potentially improving imaging of NET related disease in cardiology and in the imaging of neuroendocrine tumors. Although 18F-labeled analogues of MIBG have been reported including LMI1195, we undertook this work hypothesizing that based on its greater structural similarity to MIBG, FPOIBG might be a better analogue than LMI1195.

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“…5 The first example was reported by Coenen and colleagues, who used iodonium ylide precursors 2 derived from Meldrum’s acid (building on promising initial work patented by Satyamurthy and Barrio 5a ) to synthesize fluorophenoxyethers 3 , which are potential radioligands for PET imaging of the serotonin and norepinephrine (reuptake) transporters (Scheme 1b). 5b The concept was expanded by Vasdev, Liang and coworkers who introduced spirocyclic iodonium ylides 4 to address precursor stability issues of the earlier ylides. 5c The spirocyclic iodonium ylides are stable crystalline materials that are reactive towards fluorine-18.…”

Section: Aromatic Fluorination With Fluorine-18mentioning

confidence: 99%

“…5b The concept was expanded by Vasdev, Liang and coworkers who introduced spirocyclic iodonium ylides 4 to address precursor stability issues of the earlier ylides. 5c The spirocyclic iodonium ylides are stable crystalline materials that are reactive towards fluorine-18. They have been used to synthesize [ 18 F]fluoro(hetero)arenes bearing electron donating or electron withdrawing groups in moderate to good radiochemical yields.…”

Section: Aromatic Fluorination With Fluorine-18mentioning

confidence: 99%

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

et al. 2014

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Iodonium ylides for one-step, no-carrier-added radiofluorination of electron rich arenes, exemplified with 4-(([¹⁸F]fluorophenoxy)-phenylmethyl)piperidine NET and SERT ligands

Abstract: Iodonium ylide precursors of electron rich arenes, i.e. the NET and SERT ligands 4-((3- and 4-fluorophenoxy)phenylmethyl)piperidine, served as model compounds for the direct substitution with n.c.a. [18F]fluoride.

Cited by 71 publications

References 13 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

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

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

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Iodonium ylides for one-step, no-carrier-added radiofluorination of electron rich arenes, exemplified with 4-(([18F]fluorophenoxy)-phenylmethyl)piperidine NET and SERT ligands

Abstract: Iodonium ylide precursors of electron rich arenes, i.e. the NET and SERT ligands 4-((3- and 4-fluorophenoxy)phenylmethyl)piperidine, served as model compounds for the direct substitution with n.c.a. [18F]fluoride.

Cited by 71 publications

References 13 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

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

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

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Iodonium ylides for one-step, no-carrier-added radiofluorination of electron rich arenes, exemplified with 4-(([¹⁸F]fluorophenoxy)-phenylmethyl)piperidine NET and SERT ligands

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

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

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