Alternative synthesis for the preparation of 16α‐[18F]fluoroestradiol

We have developed a new precursor, 3,17β‐O‐bis(methoxymethyl)‐16β‐O‐p‐nitrobenzenesulfonylestriol (14c) of 16α‐[¹⁸F]fluoroestradiol ([¹⁸F]FES). Although we could not selectively protect the C17 alcohol in the presence of the C16 alcohol, we were able to prepare and chromatographically isolate the desired C16 TBDMS, C17,C3‐dimethoxymethyl (diMOM) protected estriol derivative and convert into the ultimate fluorination precursor. The MOM protective group proved to be more quickly removed than the cyclic sulfate group. The di‐MOM protective precursor at the C3 and C17 alcohols instead of a cyclic sulfate group shortened hydrolysis time. We prepared three different sulfonate precursors at C16 alcohol. After checking their reactivity in the [¹⁸F]fluorination step and considering the stability of the precursors, we obtained the best results with nosylate precursor 14c.     

Fully automated synthesis of [18F]fluoro‐dihydrotestosterone ([18F]FDHT) using the FlexLab module

Imaging of androgen receptor expression in prostate cancer using F‐18 FDHT is becoming increasingly popular. With the radiolabelling precursor now commercially available, developing a fully automated synthesis of [¹⁸F] FDHT is important. We have fully automated the synthesis of F‐18 FDHT using the iPhase FlexLab module using only commercially available components. Total synthesis time was 90 min, radiochemical yields were 25‐33% (n = 11). Radiochemical purity of the final formulation was > 99% and specific activity was > 18.5 GBq/µmol for all batches. This method can be up‐scaled as desired, thus making it possible to study multiple patients in a day. Furthermore, our procedure uses 4 mg of precursor only and is therefore cost‐effective. The synthesis has now been validated at Austin Health and is currently used for [¹⁸F]FDHT studies in patients. We believe that this method can easily adapted by other modules to further widen the availability of [¹⁸F]FDHT.     

Automated synthesis and purification of [18F]fluoro‐[di‐deutero]methyl tosylate

Automated synthetic procedures of [¹⁸F]fluoro‐[di‐deutero]methyl tosylate on a GE TRACERlab FX F‐N module and a non‐commercial synthesis module have been developed. The syntheses included azeotropic drying of the [¹⁸F]fluoride, nucleophilic ¹⁸F‐fluorination of bis(tosyloxy)‐[di‐deutero]methane, HPLC purification and subsequent formulation of the synthesized [¹⁸F]fluoro‐[di‐deutero]methyl tosylate (d₂‐[¹⁸F]FMT) in organic solvents. Automation shortened the total synthesis time to 50 min, resulting in an average radiochemical yield of about 50% and high radiochemical purity (>98%). The possible application of this procedure to commercially available synthesis modules might be of significance for the production of deuterated ¹⁸F‐fluoromethylated imaging probes in the future. Copyright © 2013 John Wiley & Sons, Ltd.     

Simplified and automatic one‐pot synthesis of 16α‐[18F]fluoroestradiol without high‐performance liquid chromatography purification

16α‐[¹⁸F]Fluoroestradiol (16α‐[¹⁸F]FES, 1) is known as a valuable tracer in molecular imaging as estrogen receptor (ER) ligand for investigation of primary and metastatic breast cancer. ER concentration in human breast tumor cells is a significant indicator for the degree of disease and is often monitored by immunoassays or in vitro ligand binding of a tumor biopsy sample. More preferable non‐invasive diagnosis is accessible using 16α‐[¹⁸F]FES (1) as PET tracer. Our aim was to develop a reliable, easy‐to‐use, remotely controlled synthesis for non carrier added (n.c.a.) 16α‐[¹⁸F]FES (1) by nucleophilic substitution using a disposable cassette for GE TRACERlab® MX_FDG. Purification of the crude product using solid phase extraction (SPE) cartridges, Oasis® WAX, HLB Plus, Sep‐Pak® C18 and Light Alumina N, allows abandonment of an HPLC purifying system. Formulation of the final product is included in the automatic synthesis. The experimental conditions for this easy‐to‐use synthesis for routine production of 16α‐[¹⁸F]FES (1) are given in detail. Within 75 min 16α‐[¹⁸F]FES (1) is produced in typically 20% n.c.a., radiochemical yield (non decay corrected). Chemical and radiochemical purity is >95% and >99%, respectively. Copyright © 2011 John Wiley & Sons, Ltd.     

Radiosynthesis of 3‐(2′‐[18F]fluoro)‐flumazenil ([18F]FFMZ)

Recently, two fluorine‐18 labelled derivatives of flumazenil were described: 5‐(2′‐[¹⁸F]fluoroethyl)‐5‐desmethylflumazenil (ethyl 8‐fluoro‐5‐[¹⁸F]fluoroethyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a] [1,4]diazepine‐3‐carboxylate; [¹⁸F]FEFMZ) and 3‐(2′‐[¹⁸F]fluoro)‐flumazenil (2′‐[¹⁸F]fluoroethyl 8‐fluoro‐5‐methyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a]‐[1,4]diazepine‐3‐carbo‐ xylate; [¹⁸F]FFMZ). Since the biodistribution data of the latter were superior to those of the former we developed a synthetic approach for [¹⁸F]FFMZ starting from a commercially available precursor, thereby obviating the need to prepare a precursor by ourselves. The following two‐step procedure was developed: First, [¹⁸F]fluoride was reacted with 2‐bromoethyl triflate using the kryptofix/acetonitrile method to yield 2‐bromo‐[¹⁸F]fluoroethane ([¹⁸F]BFE). In the second step, distilled [¹⁸F]BFE was reacted with the tetrabutylammonium salt of 3‐desethylflumazenil (8‐fluoro‐5‐methyl‐6‐oxo‐5,6‐dihydro‐4H‐benzo‐[f]imidazo[1,5‐a] [1,4]diazepine‐3‐carboxylic acid) to yield [¹⁸F]FFMZ. The synthesis of [¹⁸F]FFMZ allows for the production of up to 7 GBq of this PET‐tracer, enough to serve several patients. [¹⁸F]FFMZ synthesis was completed in less than 80 min and the radiochemical purity exceeded 98%. Copyright © 2003 John Wiley & Sons, Ltd.     

Trifluoromethanesulfonic acid,an alternative solvent medium for the direct electrophilic fluorination of DOPA: new syntheses of 6‐[18F]fluoro‐L‐DOPA and 6‐[18F]fluoro‐D‐DOPA

Previous work from this laboratory has shown that the direct fluorination of 3, 4‐dihydroxy‐phenyl‐L ‐alanine (L ‐DOPA) in anhydrous HF (aHF) or BF₃/HF with F₂ is an efficient method for the synthesis of 6‐fluoro‐L ‐DOPA. Since then, ¹⁸F‐labeled 6‐fluoro‐L ‐DOPA ([¹⁸F]6‐fluoro‐L ‐DOPA) has been used to study presynaptic dopaminergic function in the human brain and to monitor gastrointestinal carcinoid tumors. This work demonstrates that the reactivity and selectivity of F₂ toward L ‐DOPA in CF₃SO₃H is comparable with that in aHF. This new synthetic procedure has led to the production of [¹⁸F]fluoro‐L ‐DOPA and [¹⁸F]fluoro‐D‐DOPA isomers in 17±2% radiochemical yields (decay corrected with respect to [¹⁸F]F₂). The 2‐ and 6‐FDOPA isomers were separated by HPLC and subsequently characterized by ¹⁹F NMR spectroscopy. The corresponding [¹⁸F]‐FDOPA enantiomers have been obtained in clinically useful quantities by a synthetic approach that avoids the use of aHF. Copyright © 2007 John Wiley & Sons, Ltd.     

Automated preparation of 2‐[18F]fluoropropionate labeled peptides using a flexible,multi‐stage synthesis platform (iPHASE Flexlab)

Radiolabelled peptides are vital tools used in positron emission tomography imaging for the diagnosis of disease, drug discovery, and biomedical research. Peptides are typically labeled through conjugation to a radiolabelled prosthetic group, which usually necessitates complex, multi‐step procedures, especially for fluorine‐18 labeled peptides. Herein, we describe the automated synthesis and formulation of 2‐[¹⁸F]fluoropropionate labeled RGD‐peptides through use of the iPHASE Flexlab as an effective dual‐stage radiochemical synthesis module. The fully automated preparation of the monomeric RGD‐peptides, [¹⁸F]FP‐GalactoRGD and [¹⁸F]FP‐c(RGDy(SO₃)K), was accomplished in under 90 minutes with n.d.c. radiochemical yields ca. 7% from fluoride. Similarly, the automated preparation of the dimeric RGD‐peptides, [¹⁸F]F‐PRGD₂ and [¹⁸F]FP‐E(RGDy(SO₃)K)₂, was accomplished in under 105 minutes with n.d.c. yields ca. 4% from fluoride.     

Temperature effects on the stereospecificity of nucleophilic fluorination: formation of trans‐[18F]4‐fluoro‐l‐proline during the synthesis of cis‐[18F]4‐fluoro‐l‐proline

Fluorine‐18 labeled (2S,4S)‐4‐fluoro‐l ‐proline (cis‐[¹⁸F]4‐FPro) has been reported to be a potential positron emission tomography tracer to study abnormal collagen synthesis occurring in pulmonary fibrosis, osteosarcomas, mammary and colon carcinomas. In this paper, we report the stereospecific radiofluorination of (2S,4R)‐N‐tert‐butoxycarbonyl‐4‐(p‐toluenesulfonyloxy) proline methyl ester (at 110°C) to produce diastereomerically pure cis‐[¹⁸F]4‐FPro in 38% radiochemical yield at the end of a 90‐min synthesis. Investigation of the effect of temperature on the stereospecificity of nucleophilic fluorination showed that diasteriomerically pure cis‐[¹⁸F]4‐FPro or trans‐[¹⁸F]4‐FPro was produced at lower temperatures (85°C–110°C) during the fluorination of (2S,4R) or (2S,4S) precursors, respectively. However, at higher temperatures (130°C–145°C), fluorination of (2S,4R) precursor produced a mixture of cis‐[¹⁸F]4‐FPro and trans‐[¹⁸F]4‐FPro diastereomers with cis‐[¹⁸F]4‐FPro as the predominant isomer. Hydrolysis of the purified fluorinated intermediate was carried out either in one step, using 2 m triflic acid at 145°C for 10 min, or in two steps where the intermediate was heated in 1 m HCl at 110°C for 10 min followed by stirring at room temperature in 1 N NaOH for 5 min. The aqueous hydrolysis mixture was loaded onto an anion exchange column (acetate form for one‐step hydrolysis) or an ion retardation column (two‐step hydrolysis) followed by a C₁₈ Sep‐Pak® (Waters Corporation, Milford, MA, USA). Pure cis‐[¹⁸F]4‐FPro was then eluted with sterile water. We also report that epimerization of cis‐[¹⁸F]4‐FPro occurs during the two‐step hydrolysis (H⁺ followed by OH^?) of the intermediate, resulting in 5 ± 3% trans‐[¹⁸F]4‐FPro, whereas the one‐step acid hydrolysis yielded pure cis‐[¹⁸F]4‐FPro in the final product. Copyright © 2011 John Wiley & Sons, Ltd.     

A novel radiochemical approach to 1‐(2'‐deoxy‐2'‐[18F]fluoro‐β‐d‐arabinofuranosyl)cytosine (18F‐FAC)

¹⁸F‐FAC (1‐(2'‐deoxy‐2'‐[¹⁸F]fluoro‐β‐D‐arabinofuranosyl)‐cytosine) is an important 2'‐fluoro‐nucleoside‐based positron emission tomography (PET) tracer that has been used for in vivo prediction of response to the widely used cancer chemotherapy drug gemcitabine. Previously reported synthetic routes to ¹⁸F‐FAC have relied on early introduction of the ¹⁸F radiolabel prior to attachment to protected cytosine base. Considering the ¹⁸F radiochemical half‐life (110 min) and the technical challenges of multi‐step syntheses on PET radiochemistry modular systems, late‐stage radiofluorination is preferred for reproducible and reliable radiosynthesis with in vivo applications. Herein, we report the first late‐stage radiosynthesis of ¹⁸F‐FAC. Cytidine derivatives with leaving groups at the 2'‐position are particularly prone to undergo anhydro side‐product formation upon heating because of their electron density at the 2‐carbonyl pyrimidone oxygen. Our rationally developed fluorination precursor showed an improved reactivity‐to‐stability ratio at elevated temperatures. ¹⁸F‐FAC was obtained in radiochemical yields of 4.3–5.5% (n = 8, decay‐corrected from end of bombardment), with purities ≥98% and specific activities ≥63 GBq/µmol. The synthesis time was 168 min.     

Synthesis of [18F]‐labeled N‐3(substituted) thymidine analogues: N‐3([18F]fluorobutyl) thymidine ([18F]‐FBT) and N‐3([18F]fluoropentyl) thymidine ([18F]‐FPT) for PET

Syntheses of N‐3(substituted) analogues of thymidine, N‐3([¹⁸F]fluorobutyl)thymidine ([¹⁸F]‐FBT) and N‐3([¹⁸F]fluoropentyl)thymidine ([¹⁸F]‐FPT) are reported. 1,4‐Butane diol and 1,5 pentane diol were converted to their tosyl derivatives 2 and 3 followed by conversion to benzoate esters 4 and 5, respectively. Protected thymidine 1 was coupled separately with 4 and 5 to produce 6 and 7 , which were hydrolyzed to 8 and 9 , then converted to their mesylates 10 and 11 , respectively. Compounds 10 and 11 were fluorinated with n‐Bu₄N[¹⁸F] to produce 12 and 13 , which by acid hydrolysis yielded 14 and 15 , respectively. The crude products were purified by HPLC to obtain [¹⁸F]‐FBT and [¹⁸F]‐FPT. The radiochemical yields were 58–65% decay corrected (d.c.) for 14 and 46–57% (d.c.) for 15 with an average of 56% in three runs per compound. Radiochemical purity was >99% and specific activity was >74 GBq/µmol at the end of synthesis (EOS). The synthesis time was 65–75 min from the end of bombardment (EOB). Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of [18F]‐labeled adenosine analogues as potential PET imaging agents

The syntheses of adenosine analogues, 2′‐deoxy‐2′‐[¹⁸F]fluoro‐9‐β‐D ‐arabinofuranosyladenine ([¹⁸F]‐FAA) and 3′‐deoxy‐3′‐[¹⁸F]fluoro‐9‐β‐D ‐xylofuranosyladenine ([¹⁸F]‐FXA) are reported. Adenosine ( 1 ) was converted to its methoxytrityl derivatives 2 and 3 as a mixture. After separation, these derivatives were converted to their respective triflates 4 and 5 . Each triflate was reacted with tetrabutylammonium[¹⁸F]fluoride to produce 6b or 7b , which by acidic hydrolysis yielded compounds 8b and 9b . Crude preparations were purified by HPLC to obtain the desired pure products. The radiochemical yields were 10‐18% decay corrected (d. c.) for 8b and 30‐40% (d. c.) for 9b in 4 and 3 runs, respectively. Radiochemical purity was >99% and specific activity was >74 GBq/μmol at the end of synthesis (EOS). The synthesis time was 90‐95 min from the end of bombardment (EOB). Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis of 3′‐deoxy‐3′‐[18F]fluoro‐1‐β‐D‐xylofuranosyluracil ([18F]‐FMXU) for PET

The synthesis of a pyrimidine analog, 3′‐deoxy‐3′‐[¹⁸F]‐fluoro‐1‐β‐D ‐xylofuranosyluracil ([¹⁸F]‐FMXU) is reported. 5‐Methyluridine 1 was converted to its di‐methoxytrityl derivatives 2 and 3 as a mixture. After separation the 2′,5′‐di‐methoxytrityluridine 2 was converted to its 3′‐triflate 4 followed by derivatization to the respective N³‐t‐Boc product 5 . The triflate 5 was reacted with tetrabutylammonium[¹⁸F]fluoride to produce 6 , which by acid hydrolysis yielded compound 7 . The crude preparation was purified by HPLC to obtain the desired product [¹⁸F]‐FMXU. The radiochemical yields were 25–40% decay corrected (d. c.) with an average of 33% in four runs. Radiochemical purity was >99% and specific activity was >74 GBq/µmol at the end of synthesis (EOS). The synthesis time was 67–75 min from the end of bombardment (EOB). Copyright © 2005 John Wiley & Sons, Ltd.     

Radiosynthesis of 4‐[18F]fluoromethyl‐L‐phenylalanine and [18F]FET via a same strategy and automated synthesis module

Currently there is still a need for more potent amino acid analogues as tumour imaging agents for peripheral tumour imaging with PET as it was recently reported that the success of O‐(2′‐[¹⁸F]fluoroethyl)‐L ‐tyrosine ([¹⁸F]FET) is limited to brain, head and neck tumours. As the earlier described 2‐Amino‐3‐(2‐[¹⁸F]fluoromethyl‐phenyl)‐propionic acid (2‐[¹⁸F]FMP) suffered from intramolecular‐catalysed defluorination, we synthesized 2‐Amino‐3‐(4‐[¹⁸F]fluoromethyl‐phenyl)‐propionic acid (4‐[¹⁸F]FMP) as an alternative for tumour imaging with PET. Radiosynthesis of 4‐[¹⁸F]FMP, based on Br for [¹⁸F] aliphatic nucleophilic exchange, was performed with a customized modular Scintomics automatic synthesis hotbox^three system in a high overall yield of 30% and with a radiochemical purity of \gt 99%. 4‐[¹⁸F]FMP was found to be stable in its radiopharmaceutical formulation, even at high radioactivity concentrations. Additionally, for a comparative study, [¹⁸F]FET was synthesized using the same setup in 40% overall yield, with a radiochemical purity \gt 99%. The described automated radiosynthesis allows the production of two different amino acid analogues with minor alternations to the parameter settings of the automated system, rendering this unit versatile for both research and clinical practice. Copyright © 2009 John Wiley & Sons, Ltd.     

One‐step radiosynthesis of 4‐nitrophenyl 2‐[18F]fluoropropionate ([18F]NFP); improved preparation of radiolabeled peptides for PET imaging

The versatile ¹⁸F‐labeled prosthetic group, 4‐nitrophenyl 2‐[¹⁸F]fluoropropionate ([¹⁸F]NFP), was synthesized in a single step in 45 min from 4‐nitrophenyl 2‐bromopropionate, with a decay corrected radiochemical yield of 26.2% ± 2.2%. Employing this improved synthesis of [¹⁸F]NFP, [¹⁸F]GalactoRGD — the current ‘gold standard’ tracer for imaging the expression of α_Vβ₃ integrin — was prepared with high specific activity in 90 min and 20% decay corrected radiochemical yield from [¹⁸F]fluoride.     

Use of LC‐MS for the quality control of radiopharmaceuticals: example of [18F]ML10

[¹⁸F]ML10 is a promising novel low molecular weight positron emission tomography probe for apoptosis. As part of the quality control to support clinical studies for cancer therapy monitoring in the GSK Clinical Imaging Centre, a simple and sensitive liquid chromatography mass spectrometry method has been developed and validated for the quantification of total ML10 and impurity content in the final product. Chromatographic separation of ML10 and its radiolabelling precursor and impurities was achieved. Mass curves were constructed from a concentration range of ML10 and known impurities and were linear. Quantification was achieved by comparison of the area under the curve for ML10 content (m/z = 205) and the mass curve. The method was validated over a concentration range of 0.1‐1 µg/ml. Copyright © 2013 John Wiley & Sons, Ltd.     

Radiosynthesis of N5‐[18F]fluoroacetylornithine (N5‐[18F]FAO) for PET imaging of ornithine decarboxylase (ODC) in malignant tumors

Polyamines are naturally occurring polycations derived from amino acids via decarboxylation by ornithine decarboxylase (ODC). Ornithine is a substrate for ODC; decarboxylation of ornithine is inhibited by difluoromethylornithine (DFMO) and its derivatives. Polyamine contents are increased in many epithelial cancers, including breast cancer, melanoma, and prostate cancer. In order to image and measure the levels of ODC expression in malignant tumors, we have synthesized a derivative of ornithine, N⁵‐[¹⁸F]fluoroacetylornithine (N⁵‐[¹⁸F]FAO), for use in positron emission tomography. The precursor compound N²‐Boc‐N⁵‐bromoacetylornithine‐t‐butyl ester 2 was synthesized from 5‐amino‐2‐(tert‐butoxycarbonylamino)pentanoic acid, which was reacted with bromoacetyl chloride followed by esterification with tert‐butyl‐2,2,2‐trichloroacetamidate. Fluorination of the precursor produced a fluoro‐derivative, which was hydrolyzed in acid to obtain the desired compound, N⁵‐fluoroacetylornithine. The radiosynthesis of N⁵‐[¹⁸F]FAO was accomplished by radiofluorination of 2 with n‐Bu₄N[¹⁸F], followed by high‐performance liquid chromatography (HPLC) purification and then by acid hydrolysis. The radiochemical yield was 6–10% (decay corrected) with an average of 8% (n=10) at the end of synthesis. The radiochemical purity was >99%, and specific activity was >1500 mCi/µmol. The synthesis time was 95–100 min from the end of bombardment. Copyright © 2010 John Wiley & Sons, Ltd.     

[18F]6‐fluoro‐3,4‐dihydroxy‐ l‐phenylalanine – recent modern syntheses for an elusive radiotracer

[¹⁸F]6‐fluoro‐3,4‐dihydroxy‐ l ‐phenylalanine ([¹⁸F]F‐DOPA) has been known to be a useful radiotracer for over 30 years. Its widespread clinical use has been hampered by the lack of a robust, high yielding synthesis. This review summarises new developments in radiochemistry that are providing solutions to long standing problems involved in the synthesis of this important but elusive radiotracer. Considerable advances in nucleophilic synthesis have been achieved by optimising multistep strategies and using both hypervalent iodine chemistry and transition metal‐mediated fluorinations allowing for the production of high specific activity [¹⁸F]F‐DOPA.     

Radiosynthesis and ‘click’ conjugation of ethynyl‐4‐[18F]fluorobenzene — an improved [18F]synthon for indirect radiolabeling

Reproducible methods for [¹⁸F]radiolabeling of biological vectors are essential for the development of new [¹⁸F]radiopharmaceuticals. Molecules such as carbohydrates, peptides and proteins are challenging substrates that often require multi‐step indirect radiolabeling methods. With the goal of developing more robust, time saving, and less expensive procedures for indirect [¹⁸F]radiolabeling of such molecules, our group has synthesized ethynyl‐4‐[¹⁸F]fluorobenzene ([¹⁸F]2, [¹⁸F]EYFB) in a single step (14 ± 2% non‐decay corrected radiochemical yield (ndc RCY)) from a readily synthesized, shelf stable, inexpensive precursor. The alkyne‐functionalized synthon [¹⁸F]2 was then conjugated to two azido‐functionalized vector molecules via CuAAC reactions. The first ‘proof of principle’ conjugation of [¹⁸F]2 to 1‐azido‐1‐deoxy‐β‐d ‐glucopyranoside (3) gave the desired radiolabeled product [¹⁸F]4 in excellent radiochemical yield (76 ± 4% ndc RCY (11% overall)). As a second example, the conjugation of [¹⁸F]2 to matrix‐metalloproteinase inhibitor (5), which has potential in tumor imaging, gave the radiolabeled product [¹⁸F]6 in very good radiochemical yield (56 ± 12% ndc RCY (8% overall)). Total preparation time for [¹⁸F]4 and [¹⁸F]6 including [¹⁸F]F^? drying, two‐step reaction (nucleophilic substitution and CuAAC conjugation), two HPLC purifications, and two solid phase extractions did not exceed 70 min. The radiochemical purity of synthon [¹⁸F]2 and the conjugated products, [¹⁸F]4 and [¹⁸F]6, were all greater than 98%. The specific activities of [¹⁸F]2 and [¹⁸F]6 were low, 5.97 and 0.17 MBq nmol^?1, respectively.     

Microfluidic radiosynthesis and biodistribution of [18F] 2‐(5‐fluoro‐pentyl)‐2‐methyl malonic acid

Microfluidics technology has emerged as a powerful tool for the radiosynthesis of positron emission tomography (PET) and single‐photon emission computed tomography radiolabeled compounds. In this work, we have exploited a continuous flow microfluidic system (Advion, Inc., USA) for the [¹⁸F]‐fluorine radiolabeling of the malonic acid derivative, [¹⁸F] 2‐(5‐fluoro‐pentyl)‐2‐methyl malonic acid ([¹⁸F]‐FPMA), also known as [¹⁸F]‐ML‐10, a radiotracer proposed as a potential apoptosis PET imaging agent. The radiosynthesis was developed using a new tosylated precursor. Radiofluorination was initially optimized by manual synthesis and served as a basis to optimize reaction parameters for the microfluidic radiosynthesis. Under optimized conditions, radio‐thin‐layer chromatography analysis showed 79% [¹⁸F]‐fluorine incorporation prior to hydrolysis and purification. Following hydrolysis, the [¹⁸F]‐FPMA was purified by C18 Sep‐Pak, and the final product was analyzed by radio‐HPLC (high‐performance liquid chromatography). This resulted in a decay‐corrected 60% radiochemical yield and ≥98% radiochemical purity. Biodistribution data demonstrated rapid blood clearance with less than 2% of intact [¹⁸F]‐FPMA radioactivity remaining in the circulation 60 min post‐injection. Most organs showed low accumulation of the radiotracer, and radioactivity was predominately cleared through kidneys (95% in 1 h). Radio‐HPLC analysis of plasma and urine samples showed a stable radiotracer at least up to 60 min post‐injection.