Rapid synthesis of maleimide functionalized fluorine‐18 labeled prosthetic group using “radio‐fluorination on the Sep‐Pak” method

Following our recently published fluorine‐18 labeling method, “Radio‐fluorination on the Sep‐Pak”, we have successfully synthesized 6‐[¹⁸F]fluoronicotinaldehyde by passing a solution (1:4 acetonitrile: t‐butanol) of its quaternary ammonium salt precursor, 6‐(N,N,N‐trimethylamino)nicotinaldehyde trifluoromethanesulfonate ( 2 ), through a fluorine‐18 containing anion exchange cartridge (PS‐HCO₃). Over 80% radiochemical conversion was observed using 10 mg of precursor within 1 minute. The [¹⁸F]fluoronicotinaldehyde ([¹⁸F] 5 ) was then conjugated with 1‐(6‐(aminooxy)hexyl)‐1H‐pyrrole‐2,5‐dione to prepare the fluorine‐18 labeled maleimide functionalized prosthetic group, 6‐[¹⁸F]fluoronicotinaldehyde O‐(6‐(2,5‐dioxo‐2,5‐dihydro‐1H‐pyrrol‐1‐yl)hexyl) oxime, 6‐[¹⁸F]FPyMHO ([¹⁸F] 6 ). The current Sep‐Pak method not only improves the overall radiochemical yield (50 ± 9%, decay‐corrected, n = 9) but also significantly reduces the synthesis time (from 60‐90 minutes to 30 minutes) when compared with literature methods for the synthesis of similar prosthetic groups.     

A first synthesis of 18F‐radiolabeled lapatinib: a potential tracer for positron emission tomographic imaging of ErbB1/ErbB2 tyrosine kinase activity

Fluorine‐18‐labeled lapatinib has been successfully synthesized for the first time by the reaction of a dimethylformamide solution of meta‐[¹⁸F]fluorobenzylbromide with a Boc‐protected lapatinib precursor fragment. The reaction proceeded in the presence of K₂CO₃ at 110 °C for 10 min in a microwave and was followed by Boc‐group deprotection with trifluoroacetic acid. The overall radiochemical yield of the reaction starting from the radiofluorination of the iodonium salt was 8–12% (uncorrected, n = 6) in a 140‐min synthesis time.     

Syntheses of meta-[F]Fluorobenzaldehyde and meta-[F]Fluorobenzylbromide from Phenyl(3-Formylphenyl) Iodonium Salt Precursors

¹⁸F‐labeled fluorobenzaldehydes and fluorobenzylbromides are useful synthons for the preparation of positron emission tomography radiopharmaceuticals. Although ortho‐ and para‐[¹⁸F]fluorobenzaldehydes can easily be prepared with high yields, the corresponding meta‐derivatives are more problematic. In order to improve the yield of meta‐[¹⁸F]fluorobenzaldehyde, we used the corresponding diaryliodonium salt precursors, since diaryliodonium salts had already been used as precursors in the preparations of ¹⁸F‐labeled electron‐rich, as well as electron‐deficient, aromatic rings. Diaryliodonium salts with different counter ions [PhIPhCHO]X (X = Cl, Br, OTs, OTf) were synthesized. ¹⁸F radiolabeling was performed using different bases at different temperatures in the presence of a radical scavenger, 2,2,6,6‐tetramethylpiperidine‐N‐oxyl (TEMPO). The best conversion (～80%) to meta‐[¹⁸F]fluorobenzaldehyde was obtained using CsHCO₃ base at a reaction temperature of 110°C. To study iodonium salt counter ion effects on radiofluorination, each precursor was separately treated with Cs[¹⁸F]F/CsHCO₃ in DMF at 110°C for 5 min in the presence of TEMPO. Our observed reactivity order was OTsMeta‐[¹⁸F]fluorobenzaldehyde thus obtained was reduced to the corresponding alcohol with aqueous NaBH₄ at room temperature and then converted to meta‐[¹⁸F]fluorobenzylbromide using triphenylphosphine dibromide. Formation of meta‐[¹⁸F]fluorobenzylbromide was confirmed using high‐performance liquid chromatography and the desired product was purified on a silica Sep ‐ Pak^® plus cartridge. Published in 2011 by John Wiley & Sons, Ltd.     

Evaluation of a procaspase-3 activator with hydroxyurea or temozolomide against high-grade meningioma in cell culture and canine cancer patients

BackgroundHigh-grade meningioma is an aggressive type of brain cancer that is often recalcitrant to surgery and radiotherapy, leading to poor overall survival. Currently, there are no FDA-approved drugs for meningioma, highlighting the need for new therapeutic options, but development is challenging due to the lack of predictive preclinical models.MethodsTo leverage the known overexpression of procaspase-3 in meningioma, PAC-1, a blood-brain barrier penetrant procaspase-3 activator, was evaluated for its ability to induce apoptosis in meningioma cells. To enhance the effects of PAC-1, combinations with either hydroxyurea or temozolomide were explored in cell culture. Both combinations were further investigated in small groups of canine meningioma patients and assessed by MRI, and the novel apoptosis tracer, [¹⁸F]C-SNAT4, was evaluated in patients treated with PAC-1 + HU.ResultsIn meningioma cell lines in culture, PAC-1 + HU are synergistic while PAC-1 + TMZ show additive-to-synergistic effects. In canine meningioma patients, PAC-1 + HU led to stabilization of disease and no change in apoptosis within the tumor, whereas PAC-1 + TMZ reduced tumor burden in all three canine patients treated.ConclusionsOur results suggest PAC-1 + TMZ as a potentially efficacious combination for the treatment of human meningioma, and also demonstrate the utility of including pet dogs with meningioma as a means to assess anticancer strategies for this common brain tumor.     

Synthesis of ApoSense compound [18F]2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-(fluoromethyl)butanoic acid ([18F]NST732) by nucleophilic ring opening of an aziridine precursor

IntroductionThe small molecule 2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-(fluoromethyl)butanoic acid (NST732) is a member of the ApoSense family of compounds, capable of selective targeting, binding and accumulation within cells undergoing apoptotic cell death. It has application in molecular imaging and blood clotting particularly for monitoring antiapoptotic drug treatments. We are investigating a fluorine-18-radiolabeled analog of this compound for positron emission tomography studies.MethodsWe prepared the tosylate precursor methyl 2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-(tosyloxymethyl)butanoate (4) to synthesize fluorine-18-labeled NST732. Fluorination reaction of the tosylate precursor in 1:1 acetonitrile:dimethylsulfoxide with tetrabutyl ammonium fluoride proceeds through an aziridine intermediate (4A) to afford two regioisomers: 2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-fluorobutanoate (5) and methyl 2-(5-(dimethylamino)naphthalene-1-sulfonamido)-2-(fluoromethyl)butanoate (6). Acid hydrolysis of the fluoromethylbutanoate (6) isomer produced NST732. As the fluorination reaction of the tosylate precursor proceeds through an aziridine intermediate (4A) and the fluorination conceivably could be done directly on the aziridine, we have separately prepared an aziridine precursor (4A). Fluorine-18 labeling of the aziridine precursor (4A) was performed with [¹⁸F]tetrabutyl ammonium fluoride to afford the same two regioisomers (5 and 6). The [¹⁸F]2-((5-dimethylamino)naphthalene-1-sulfonamido)methyl)-2-fluorobutanoic acid (NST732) was then obtained by the hydrolysis of corresponding [¹⁸F]-labeled ester (6) with 6 N hydrochloric acid.ResultsTwo regioisomers obtained from the fluorination reaction of aziridine were easily separated by high-performance liquid chromatography. The total radiochemical yield was 15%±3% (uncorrected, n=18) from the aziridine precursor in a 70-min synthesis time with a radiochemical purity >99%.ConclusionFluorine-18-labeled ApoSense compound [¹⁸F]NST732 is prepared in moderate yield by direct fluorination of an aziridine precursor.     

An efficient new method for the synthesis of 3‐[18F]fluoro‐4‐aminopyridine via Yamada‐Curtius rearrangement

4‐Aminopyridine is a clinically approved drug to improve motor symptoms in multiple sclerosis . A fluorine‐18‐labeled derivative of this drug, 3‐[¹⁸F]fluoro‐4‐aminopyridine, is currently under investigation for positron emission tomography (PET) imaging of demyelination. Herein, the Yamada‐Curtius reaction has been successfully applied for the preparation of this PET radioligand with a better radiochemical yield and improved specific activity. The overall radiochemical yield was 5 to 15% (n = 12, uncorrected) with a specific activity of 37 to 148 GBq/μmol (end of synthesis) in a 90 minute synthesis time. It is expected that this 1 pot Yamada‐Curtius reaction can be used to prepare similar fluorine‐18‐labeled amino substituted heterocycles.     

An azeotropic drying‐free approach for copper‐mediated radiofluorination without addition of base

Copper‐mediated radiofluorination provides a quick and versatile approach for ¹⁸F‐labeling of arenes and heteroarenes. However, this method is known to be base sensitive, which has been a barrier for preparative scale radiosynthesis. In this report, we provide an approach for copper‐mediated radiofluorination without azeotropic drying or adding a base. [¹⁸F]Fluoride trapped on a PS‐HCO₃ Sep‐Pak was quantitatively eluted with a solution of 4‐dimethylaminopyridinium trifluoromethanesulfonate (DMAP·OTf) in anhydrous N,N‐dimethylformamide (DMF). The eluted solution was directly used for copper‐mediated radiofluorination. Twelve boronic ester substrates were tested, yielding fluorinated products in 27% to 83% radiochemical yield based on HPLC analysis. This approach was successfully applied to the radiosynthesis of [¹⁸F]flumazenil, a well‐known positron emission tomography (PET) tracer for imaging central benzodiazepine receptors, with a radiochemical yield of 47%. This highly efficient protocol significantly augments the powerful copper‐mediated radiofluorination approach.