Automated Optimized Synthesis of [18F]FLT Using Non-Basic Phase-Transfer Catalyst with Reduced Precursor Amount

3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) is a positron emission tomography (PET) tracer useful for tumor proliferation assessment for a number of cancers, particularly in the cases of brain, lung, and breast tumors. At present [18F], FLT is commonly prepared by means of the nucleophilic radiofluorination of 3-N-Boc-5′-O-DMT-3′-O-nosyl thymidine precursor in the presence of a phase-transfer catalyst, followed by an acidic hydrolysis. To achieve high radiochemical yield, relatively large amounts of precursor (20–40 mg) are commonly used, leading to difficulties during purification steps, especially if a solid-phase extraction (SPE) approach is attempted. The present study describes an efficient method for [18F]FLT synthesis, employing tetrabutyl ammonium tosylate as a non-basic phase-transfer catalyst, with a greatly reduced amount of precursor employed. With a reduction of the precursor amount contributing to lower amounts of synthesis by-products in the reaction mixture, an SPE purification procedure using only two commercially available cartridges—OASIS HLB 6cc and Sep-Pak Alumina N Plus Light—has been developed for use on the GE TRACERlab FX N Pro synthesis module. [18F]FLT was obtained in radiochemical yield of 16 ± 2% (decay-corrected) and radiochemical purity >99% with synthesis time not exceeding 55 min. The product was formulated in 16 mL of normal saline with 5% ethanol (v/v). The amounts of chemical impurities and residual solvents were within the limits established by European Pharmacopoeia. The procedure described compares favorably with previously reported methods due to simplified automation, cheaper and more accessible consumables, and a significant reduction in the consumption of an expensive precursor.

[1]  V. Goh,et al.  Role of 3'-Deoxy-3'-[18F] Fluorothymidine Positron Emission Tomography-Computed Tomography as a Predictive Biomarker in Argininosuccinate Synthetase 1-Deficient Thoracic Cancers Treated With Pegargiminase , 2022, JTO clinical and research reports.

[2]  M. Ray,et al.  Automated Radiochemical Synthesis of Pharmaceutical Grade [18 F]FLT using 3-N-Boc-5'-O-dimethoxytrityl-3'-O-nosyl-thymidine precursor and its Sep-Pak® Purification employing Selective Elution from Reversed Phase. , 2022, Journal of labelled compounds & radiopharmaceuticals.

[3]  R. Krasikova,et al.  Automated synthesis of the 16α-[18F]fluoroestradiol ([18F]FES): minimization of precursor amount and resulting benefits , 2020 .

[4]  O. Fedorova,et al.  Tetrabutylammonium tosylate as inert phase-transfer catalyst: The key to high efficiency SN2 radiofluorinations. , 2020, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[5]  R. Krasikova,et al.  A fully automated azeotropic drying free synthesis of O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) using tetrabutylammonium tosylate. , 2019, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[6]  R. Krasikova,et al.  Automated SPE-based synthesis of 16α-[18F]fluoroestradiol without HPLC purification step. , 2018, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[7]  S. G. Patching,et al.  Nucleoside transporters in PET imaging of proliferating cancer cells using 3ꞌ-deoxy-3ꞌ-[18F]fluoro-L-thymidine , 2018 .

[8]  G. Shen,et al.  Correlations of 18F-FDG and 18F-FLT uptake on PET with Ki-67 expression in patients with lung cancer: a meta-analysis , 2018, Acta radiologica.

[9]  I. Tsougos,et al.  18F-fluorothymidine PET imaging in gliomas: an update , 2017, Annals of Nuclear Medicine.

[10]  A. Ouadi,et al.  Automated and efficient radiosynthesis of [(18)F]FLT using a low amount of precursor. , 2016, Nuclear medicine and biology.

[11]  W. Oyen,et al.  A systematic review on [(18)F]FLT-PET uptake as a measure of treatment response in cancer patients. , 2016, European journal of cancer.

[12]  E. McKinley,et al.  High-yielding, automated production of 3'-deoxy-3'-[(18)F]fluorothymidine using a modified Bioscan Coincidence FDG reaction module. , 2015, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[13]  M. Muzi,et al.  Applications of PET imaging with the proliferation marker [18F]-FLT. , 2015, The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of....

[14]  B. Solomon,et al.  Effect of Platinum-Based Chemoradiotherapy on Cellular Proliferation in Bone Marrow and Spleen, Estimated by 18F-FLT PET/CT in Patients with Locally Advanced Non–Small Cell Lung Cancer , 2014, The Journal of Nuclear Medicine.

[15]  F. Bertagna,et al.  The role of F-18-fluorothymidine PET in oncology , 2013, Clinical and Translational Imaging.

[16]  Yuka Yamamoto,et al.  Usefulness of 3′-Deoxy-3′-18F-Fluorothymidine PET for Predicting Early Response to Chemoradiotherapy in Head and Neck Cancer , 2012, The Journal of Nuclear Medicine.

[17]  A. Bogni,et al.  Simple preparation and purification of ethanol-free solutions of 3'-deoxy-3'-[18F]fluorothymidine by means of disposable solid-phase extraction cartridges. , 2012, Nuclear medicine and biology.

[18]  Federico Turkheimer,et al.  [18F]-3′Deoxy-3′-Fluorothymidine Positron Emission Tomography and Breast Cancer Response to Docetaxel , 2011, Clinical Cancer Research.

[19]  T. Saga,et al.  PET/CT with 3′-deoxy-3′-[18F]fluorothymidine for lung cancer patients receiving carbon-ion radiotherapy , 2011, Nuclear medicine communications.

[20]  S. Oh,et al.  Simple and highly efficient synthesis of 3′-deoxy-3′-[18F]fluorothymidine using nucleophilic fluorination catalyzed by protic solvent , 2007, European Journal of Nuclear Medicine and Molecular Imaging.

[21]  Dong Wook Kim,et al.  A new class of SN2 reactions catalyzed by protic solvents: Facile fluorination for isotopic labeling of diagnostic molecules. , 2006, Journal of the American Chemical Society.

[22]  J. Yeo,et al.  Fully automated synthesis system of 3'-deoxy-3'-[18F]fluorothymidine. , 2004, Nuclear medicine and biology.

[23]  Dae Hyuk Moon,et al.  High radiochemical yield synthesis of 3'-deoxy-3'-[18F]fluorothymidine using (5'-O-dimethoxytrityl-2'-deoxy-3'-O-nosyl-beta-D-threo pentofuranosyl)thymine and its 3-N-BOC-protected analogue as a labeling precursor. , 2003, Nuclear medicine and biology.

[24]  U. Haberkorn,et al.  A new precursor for the radiosynthesis of [18F]FLT. , 2002, Nuclear medicine and biology.

[25]  Otto Muzik,et al.  Imaging proliferation in vivo with [F-18]FLT and positron emission tomography , 1998, Nature Medicine.

[26]  L. T. C. Nascimento,et al.  Comparison between Two Ethanolic Solutions for 3’-Deoxy-3’-[ 18 F]Fluorothymidine Elution , 2017 .