An improved automated one-pot synthesis of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) based on a purification by cartridges

A. Bogni, L. Laera, C. Cucchi, R. Iwata, E. Seregni, C. Pascali

Research output: Contribution to journalArticle

Abstract

Introduction: O-(2-[18F]Fluoroethyl)-L-tyrosine ([18F]FET) is an established radiotracer used for oncology investigations by Positron Emission Tomography (PET). Main limitations to its widespread use are the synthesis itself (time; cost; radiochemical yield; complexity) and a troublesome and time-consuming HPLC purification. Aim of this work was to improve the preparation overall efficiency and, most important, to achieve an efficient and reliable purification by means of disposable cartridges. Methods: [18F]FET was synthesized by direct nucleophilic radiofluorination of O-(2-tosyloxy-ethyl)-N-trityl-L-tyrosine t-butylester (TET) followed by acid hydrolysis with HCl. Several conditions and materials were tested for the synthesis and purification step. For the latter, a number of different commercial cartridges, varying in amount, particulate size and adsorbent, were examined. Best results were obtained by a combination of STRATA-X, tC18 and QMA cartridges. Results: Starting from only 5 mg of TET, up to 11 GBq of injectable solutions of [18F]FET were produced within 36 min with 54–65% radiochemical yields and radiochemical purities >99%. No D-form was observed by chiral HPLC. Chemical purity was 1–2 order of magnitude below the limits imposed by the European Pharmacopoeia's monograph on [18F]FET. A radiochemical purity decrease by radiolysis, observed only on relatively large batches of [18F]FET, was efficiently suppressed by preloading in the receiving final vial a small amount of ethanol (<2% v/v). Conclusions: By combining improvements to a known synthetic route with a novel cartridge-based purification, [18F]FET was obtained in a very efficient and reproducible way. The whole process was easily implemented on a commercial automated module presently used for [18F]FDG production. Advances in knowledge and implications for patient care: A few drawbacks regarding the HPLC conditions recommended in the European Pharmacopoeia were highlighted. An alternative method able to cope with them is herein proposed The simplified preparation herein described is expected to encourage a more widespread clinical use of [18F]FET.

Original languageEnglish
Pages (from-to)11-19
Number of pages9
JournalNuclear Medicine and Biology
Volume72-73
DOIs
Publication statusPublished - May 1 2019

Fingerprint

Pharmacopoeias
High Pressure Liquid Chromatography
Fluorodeoxyglucose F18
Positron-Emission Tomography
Tyrosine
Patient Care
Hydrolysis
Ethanol
Costs and Cost Analysis
Injections
Acids
O-(2-fluoroethyl)tyrosine

Keywords

  • Automation
  • Cartridge purification
  • HPLC analysis
  • PET amino acids
  • Radiolysis
  • [F]FET

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

An improved automated one-pot synthesis of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) based on a purification by cartridges. / Bogni, A.; Laera, L.; Cucchi, C.; Iwata, R.; Seregni, E.; Pascali, C.

In: Nuclear Medicine and Biology, Vol. 72-73, 01.05.2019, p. 11-19.

Research output: Contribution to journalArticle

@article{81021e38dafd4b608df9ea29817864d7,
title = "An improved automated one-pot synthesis of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) based on a purification by cartridges",
abstract = "Introduction: O-(2-[18F]Fluoroethyl)-L-tyrosine ([18F]FET) is an established radiotracer used for oncology investigations by Positron Emission Tomography (PET). Main limitations to its widespread use are the synthesis itself (time; cost; radiochemical yield; complexity) and a troublesome and time-consuming HPLC purification. Aim of this work was to improve the preparation overall efficiency and, most important, to achieve an efficient and reliable purification by means of disposable cartridges. Methods: [18F]FET was synthesized by direct nucleophilic radiofluorination of O-(2-tosyloxy-ethyl)-N-trityl-L-tyrosine t-butylester (TET) followed by acid hydrolysis with HCl. Several conditions and materials were tested for the synthesis and purification step. For the latter, a number of different commercial cartridges, varying in amount, particulate size and adsorbent, were examined. Best results were obtained by a combination of STRATA-X, tC18 and QMA cartridges. Results: Starting from only 5 mg of TET, up to 11 GBq of injectable solutions of [18F]FET were produced within 36 min with 54–65{\%} radiochemical yields and radiochemical purities >99{\%}. No D-form was observed by chiral HPLC. Chemical purity was 1–2 order of magnitude below the limits imposed by the European Pharmacopoeia's monograph on [18F]FET. A radiochemical purity decrease by radiolysis, observed only on relatively large batches of [18F]FET, was efficiently suppressed by preloading in the receiving final vial a small amount of ethanol (<2{\%} v/v). Conclusions: By combining improvements to a known synthetic route with a novel cartridge-based purification, [18F]FET was obtained in a very efficient and reproducible way. The whole process was easily implemented on a commercial automated module presently used for [18F]FDG production. Advances in knowledge and implications for patient care: A few drawbacks regarding the HPLC conditions recommended in the European Pharmacopoeia were highlighted. An alternative method able to cope with them is herein proposed The simplified preparation herein described is expected to encourage a more widespread clinical use of [18F]FET.",
keywords = "Automation, Cartridge purification, HPLC analysis, PET amino acids, Radiolysis, [F]FET",
author = "A. Bogni and L. Laera and C. Cucchi and R. Iwata and E. Seregni and C. Pascali",
year = "2019",
month = "5",
day = "1",
doi = "10.1016/j.nucmedbio.2019.05.006",
language = "English",
volume = "72-73",
pages = "11--19",
journal = "Nuclear Medicine and Biology",
issn = "0969-8051",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - An improved automated one-pot synthesis of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) based on a purification by cartridges

AU - Bogni, A.

AU - Laera, L.

AU - Cucchi, C.

AU - Iwata, R.

AU - Seregni, E.

AU - Pascali, C.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Introduction: O-(2-[18F]Fluoroethyl)-L-tyrosine ([18F]FET) is an established radiotracer used for oncology investigations by Positron Emission Tomography (PET). Main limitations to its widespread use are the synthesis itself (time; cost; radiochemical yield; complexity) and a troublesome and time-consuming HPLC purification. Aim of this work was to improve the preparation overall efficiency and, most important, to achieve an efficient and reliable purification by means of disposable cartridges. Methods: [18F]FET was synthesized by direct nucleophilic radiofluorination of O-(2-tosyloxy-ethyl)-N-trityl-L-tyrosine t-butylester (TET) followed by acid hydrolysis with HCl. Several conditions and materials were tested for the synthesis and purification step. For the latter, a number of different commercial cartridges, varying in amount, particulate size and adsorbent, were examined. Best results were obtained by a combination of STRATA-X, tC18 and QMA cartridges. Results: Starting from only 5 mg of TET, up to 11 GBq of injectable solutions of [18F]FET were produced within 36 min with 54–65% radiochemical yields and radiochemical purities >99%. No D-form was observed by chiral HPLC. Chemical purity was 1–2 order of magnitude below the limits imposed by the European Pharmacopoeia's monograph on [18F]FET. A radiochemical purity decrease by radiolysis, observed only on relatively large batches of [18F]FET, was efficiently suppressed by preloading in the receiving final vial a small amount of ethanol (<2% v/v). Conclusions: By combining improvements to a known synthetic route with a novel cartridge-based purification, [18F]FET was obtained in a very efficient and reproducible way. The whole process was easily implemented on a commercial automated module presently used for [18F]FDG production. Advances in knowledge and implications for patient care: A few drawbacks regarding the HPLC conditions recommended in the European Pharmacopoeia were highlighted. An alternative method able to cope with them is herein proposed The simplified preparation herein described is expected to encourage a more widespread clinical use of [18F]FET.

AB - Introduction: O-(2-[18F]Fluoroethyl)-L-tyrosine ([18F]FET) is an established radiotracer used for oncology investigations by Positron Emission Tomography (PET). Main limitations to its widespread use are the synthesis itself (time; cost; radiochemical yield; complexity) and a troublesome and time-consuming HPLC purification. Aim of this work was to improve the preparation overall efficiency and, most important, to achieve an efficient and reliable purification by means of disposable cartridges. Methods: [18F]FET was synthesized by direct nucleophilic radiofluorination of O-(2-tosyloxy-ethyl)-N-trityl-L-tyrosine t-butylester (TET) followed by acid hydrolysis with HCl. Several conditions and materials were tested for the synthesis and purification step. For the latter, a number of different commercial cartridges, varying in amount, particulate size and adsorbent, were examined. Best results were obtained by a combination of STRATA-X, tC18 and QMA cartridges. Results: Starting from only 5 mg of TET, up to 11 GBq of injectable solutions of [18F]FET were produced within 36 min with 54–65% radiochemical yields and radiochemical purities >99%. No D-form was observed by chiral HPLC. Chemical purity was 1–2 order of magnitude below the limits imposed by the European Pharmacopoeia's monograph on [18F]FET. A radiochemical purity decrease by radiolysis, observed only on relatively large batches of [18F]FET, was efficiently suppressed by preloading in the receiving final vial a small amount of ethanol (<2% v/v). Conclusions: By combining improvements to a known synthetic route with a novel cartridge-based purification, [18F]FET was obtained in a very efficient and reproducible way. The whole process was easily implemented on a commercial automated module presently used for [18F]FDG production. Advances in knowledge and implications for patient care: A few drawbacks regarding the HPLC conditions recommended in the European Pharmacopoeia were highlighted. An alternative method able to cope with them is herein proposed The simplified preparation herein described is expected to encourage a more widespread clinical use of [18F]FET.

KW - Automation

KW - Cartridge purification

KW - HPLC analysis

KW - PET amino acids

KW - Radiolysis

KW - [F]FET

UR - http://www.scopus.com/inward/record.url?scp=85067942471&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067942471&partnerID=8YFLogxK

U2 - 10.1016/j.nucmedbio.2019.05.006

DO - 10.1016/j.nucmedbio.2019.05.006

M3 - Article

C2 - 31255875

AN - SCOPUS:85067942471

VL - 72-73

SP - 11

EP - 19

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

SN - 0969-8051

ER -