Application of Palladium-Mediated 18F-Fluorination to PET Radiotracer Development: Overcoming Hurdles to Translation

Kamlet, Adam S.; Neumann, Constanze N.; Lee, Eunsung; Carlin, Stephen M.; Moseley, Christian K.; Stephenson, Nickeisha A.; Hooker, Jacob M.; Ritter, Tobias

doi:10.1371/journal.pone.0059187

Cited by 92 publications

(75 citation statements)

References 46 publications

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“…79,80 The 2,4,5-trifluorophenyl moiety of sitagliptin (159) is an important structural element that conferred an improved safety profile compared to the 2,5-difluoro homologue. 80b The 2,4,5-trifluorophenyl ring occupies the S1 subsite of the enzyme, and the 2-fluoro atom is close to the side chain N-Hs of Arg125 and Asn710, with the distance between this fluorine atom and the nitrogen atom of Asn710 measured as 3.2 Å ( Figure 22).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Applications of Fluorine in Medicinal Chemistry

et al. 2015

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The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, (18)F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Applications of Fluorine in Medicinal Chemistry

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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“…3 Pd(IV) complex 1 is the first reagent that can be synthesized from fluoride and, subsequently, transfers its entire fluorine content in an electrophilic fluorination reaction suitable for late-stage 18 F fluorination. 4 Here, we describe an experimentally substantiated proposal regarding the unusual mechanism by which electrophilic fluorination proceeds and outline the scope and limitations of complex 1 as electrophilic fluorinating reagent for fluorination of several nucleophiles.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of electrophilic fluorination with Pd(iv): fluoride capture and subsequent oxidative fluoride transfer

et al. 2014

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Electrophilic fluorinating reagents derived from fluoride are desirable for the synthesis of 18F-labeled molecules for positron emission tomography (PET). Here, we study the mechanism by which a Pd(IV)-complex captures fluoride and subsequently transfers it to nucleophiles. The intermediate Pd(IV)-F is formed with high rates even at the nano- to micromolar fluoride concentrations typical for radiosyntheses with 18F due to fast formation of an outer-sphere complex between fluoride and Pd(IV). The subsequent fluorine transfer from the Pd(IV)-F complex is proposed to proceed through an unusual SET/fluoride transfer/SET mechanism. The findings detailed in this manuscript provide a theoretical foundation suitable for addressing a more general approach for electrophilic fluorination with high specific activity 18F PET imaging.

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Application of Palladium-Mediated 18F-Fluorination to PET Radiotracer Development: Overcoming Hurdles to Translation

Cited by 92 publications

References 46 publications

Applications of Fluorine in Medicinal Chemistry

Applications of Fluorine in Medicinal Chemistry

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

Mechanism of electrophilic fluorination with Pd(iv): fluoride capture and subsequent oxidative fluoride transfer

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