Silicon-[18F]Fluorine Radiochemistry: Basics, Applications and Challenges

Wängler, Carmen; Kostikov, Alexey; Zhu, Jun; Chin, Joshua; Wängler, Björn; Schirrmacher, Ralf

doi:10.3390/app2020277

Cited by 42 publications

(62 citation statements)

References 50 publications

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“…has attracted high attention due to the strong nature of the Si-18 F bond and more important its fast and efficient 18 Fradiolabeling as well as the simple product workup, enabling a kit-like synthesis of 18 Flabeled peptides. [19][20][21][22][23][24][25] Its characteristics such as the simple one-step 19 F-18 F-isotopic exchange reaction under very mild labeling conditions (5 min at ambient temperature) producing no side-products, the small precursor amounts (nmol range) required as well as high achievable radiochemical yields and specific activities of the obtained radiolabeled compounds illustrate the advantages of this 18 F-labeling chemistry. However, a structural prerequisite for a high hydrolytic stability of the 18 F-Si bond are the aromatic and two tert-butyl groups on the silicon atom ( Figure 1A), considerably increasing the overall lipophilicity of SiFA-modified substances.…”

Section: Introductionmentioning

confidence: 96%

Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR-Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics

Litau¹,

Niedermoser²,

Vogler³

et al. 2015

Bioconjugate Chem.

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The Silicon-Fluoride-Acceptor (SiFA)-(18)F-labeling strategy has been shown before to enable the straightforward and efficient (18)F-labeling of complex biologically active substances such as proteins and peptides. Especially in the case of peptides, the radiolabeling proceeds kit-like in short reaction times and without the need of complex product workup. SiFA-derivatized, (18)F-labeled Tyr(3)-octreotate (TATE) derivatives demonstrated, besides strong somatostatin receptor (SSTR) binding, favorable in vivo pharmacokinetics as well as excellent tumor visualization by PET imaging. In this study, we intended to determine the influence of the underlying molecular design and used molecular scaffolds of SiFAlin-TATE derivatives on SSTR binding as well as on the in vivo pharmacokinetics of the resulting (18)F-labeled peptides. For this purpose, new SiFAlin-(Asp)n-PEG1-TATE analogs (where n = 1-4) were synthesized, efficiently radiolabeled with (18)F in a kit-like manner and obtained in radiochemical yields of 70-80%, radiochemical purities of ≥97%, and nonoptimized specific activities of 20.1-45.2 GBq/μmol within 20-25 min starting from 0.7-1.5 GBq of (18)F. In the following, the radiotracer's lipophilicities and stabilities in human serum were determined. Furthermore, the SSTR-specific binding affinities were evaluated by a competitive displacement assay on SSTR-positive AR42J cells. The obtained in vitro results support the assumption that aspartic acids are able to considerably increase the radiotracer's hydrophilicity and that their number does not affect the SSTR binding potential of the TATE derivatives. The most promising tracer (18)F-SiFAlin-Asp3-PEG1-TATE [(18)F]6 (LogD = -1.23 ± 0.03, IC50 = 20.7 ± 2.5 nM) was further evaluated in vivo in AR42J tumor-bearing nude mice via PET/CT imaging against the clinical gold standard (68)Ga-DOTATATE as well as the previously developed SiFAlin-TATE derivative [(18)F]3. The results of these evaluations showed that [(18)F]6-although showing very similar chemical and in vitro properties to [(18)F]3-exhibits not only a slowed renal clearance compared to [(18)F]3, but also a higher absolute tumor uptake compared to (68)Ga-DOTATATE, and furthermore enables excellent tumor visualization with high image resolution. These results emphasize the importance of systematic study of the influence of molecular design and applied structure elements of peptidic radiotracers, as these may considerably influence in vivo pharmacokinetics while not affecting other parameters such as radiochemistry, lipophilicity, serum stability, or receptor binding potential.

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Section: Introductionmentioning

confidence: 96%

Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR-Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics

Litau¹,

Niedermoser²,

Vogler³

et al. 2015

Bioconjugate Chem.

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“…Fluorine-18, widely used in clinical positron emission tomography (PET) imaging in biomedical science because its optimal physical decay properties (t1/2 = 110 min, E β+, max = 0.6 MeV) facilitates multistep syntheses and PET images of high quality. Wångler and coworkers [18] in their review Silicon-[ Similarly it was also difficult to correlate the position of fluorine substitution on the benzene ring or the effect of multiple fluorine substituents with antibacterial activity and logP values. Can aromatic ring fluorine/hydrogen exchange influence membrane permeability?…”

Section: Synthesis/applications Of Organo-fluorine Moleculesmentioning

confidence: 99%

Special Feature Organo-Fluorine Chemical Science

Hügel

Jackson

2012

Applied Sciences

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Inventing the Fluorine FutureFluorine is the 13th most abundant element and, with other fluorine containing functional groups, is a most effective element in biological substances, pharmaceuticals, agrochemicals, liquid crystals, dyes, polymers and a wide range of consumer products. This reflects its resistance to metabolic change due to the strength of the C-F bond providing biological stability and the application of its nonstick-interfacial physical characteristics. Its introduction often remains a synthetic challenge. The widespread use of organofluorines has increased the demand for the development of practical and simple reagents and experimental strategies for the incorporation of fluorine into all types of molecular structures and this was the reasoning behind this special feature on Organo-Fluorine Chemical Science.The contributed articles belong to two broad groups: (i) preparation of fluorine materials, polymers; (ii) the synthesis/applications of organo-fluorine molecules. Fluorine-Fatness-Due to Lack of FitnessTheoretical [1] and experimental observations to explain the molecular origins of fluorocarbon hydrophobicity suggest that the hydrophobicity of a fluorocarbon, whether the interaction with water is as solute or as surface, is due to its "fatness". In solution, the extra work of cavity formation to accommodate a fluorocarbon, compared to a hydrocarbon, is not offset by enhanced energetic interactions with water. The enhanced hydrophobicity of fluorinated surfaces arises because fluorocarbons pack less densely on surfaces leading to poorer van der Waals interactions with water. The interaction of water with a hydrophobic solute/surface is primarily a function of van der Waals interactions and is substantially independent of electrostatic interactions. This independence is primarily due to the strong tendency of water at room temperature to maintain its hydrogen bonding network structure at an interface lacking hydrophilic sites. OPEN ACCESS

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“…1 Low molecular weight 18 F-labeled organosilanes are now appearing as PET radiotracers, including one example of a radiotracer for imaging 5-HT 1A receptors in brain. 2 Moreover, small [ 18 F]organofluorosilanes are finding use as synthons for labeling peptides and proteins.…”

Section: Introductionmentioning

confidence: 99%

Crown Ether Nucleophilic Catalysts (CENCs): Agents for Enhanced Silicon Radiofluorination

et al. 2017

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New bifunctional phase transfer agents were synthesized and investigated for their abilities to promote rapid fluorination at silicon. These agents, dubbed crown ether nucleophilic catalysts (CENCs), are 18-crown-6 derivatives containing a side-arm and a potentially nucleophilic hydroxyl group. These CENCs proved efficacious in the fluorination of hindered silicon substrates, with fluorination yields dependent on the length of linker connecting the metal chelating unit to the hydroxyl group. The efficacy of these CENCs was also demonstrated for rapid radiofluorination under mild conditions for eventual application in molecular imaging with positron emission tomography (PET). The hydrolysis-resistant aryl silicon fragment is promising as a convenient synthon for labeling potential PET radiotracers.

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Silicon-[18F]Fluorine Radiochemistry: Basics, Applications and Challenges

Cited by 42 publications

References 50 publications

Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR-Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics

Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR-Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics

Special Feature Organo-Fluorine Chemical Science

Crown Ether Nucleophilic Catalysts (CENCs): Agents for Enhanced Silicon Radiofluorination

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