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

Babak Behnam Azad, Rezwan Ashique, N. Renée Labiris, Raman Chirakal

Research output: Contribution to journalArticle

Abstract

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 2m triflic acid at 145°C for 10min, or in two steps where the intermediate was heated in 1m HCl at 110°C for 10min followed by stirring at room temperature in 1 N NaOH for 5min. 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 C 18 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.

Original languageEnglish (US)
Pages (from-to)23-28
Number of pages6
JournalJournal of Labelled Compounds and Radiopharmaceuticals
Volume55
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

Fingerprint

Fluorination
Halogenation
Proline
Thermal effects
Hydrolysis
Temperature
Positron emission tomography
Fluorine
Water
Pulmonary Fibrosis
Osteosarcoma
Isomers
Positron-Emission Tomography
Anions
fluoro-proline
Colon
Esters
Acetates
Collagen
Ions

Keywords

  • fluorine-18
  • fluoro- l -proline
  • nucleophilic fluorination
  • PET
  • pulmonary fibrosis
  • radiolabeling

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Radiology Nuclear Medicine and imaging
  • Drug Discovery
  • Spectroscopy
  • Organic Chemistry

Cite this

@article{2c076f1c3d6f482cac7c3a774082469b,
title = "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",
abstract = "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 2m triflic acid at 145°C for 10min, or in two steps where the intermediate was heated in 1m HCl at 110°C for 10min followed by stirring at room temperature in 1 N NaOH for 5min. 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 C 18 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.",
keywords = "fluorine-18, fluoro- l -proline, nucleophilic fluorination, PET, pulmonary fibrosis, radiolabeling",
author = "{Behnam Azad}, Babak and Rezwan Ashique and Labiris, {N. Ren{\'e}e} and Raman Chirakal",
year = "2012",
month = "1",
doi = "10.1002/jlcr.1947",
language = "English (US)",
volume = "55",
pages = "23--28",
journal = "Journal of Labelled Compounds and Radiopharmaceuticals",
issn = "0362-4803",
publisher = "John Wiley and Sons Ltd",
number = "1",

}

TY - JOUR

T1 - Temperature effects on the stereospecificity of nucleophilic fluorination

T2 - Formation of trans-[ 18F]4-fluoro-l-proline during the synthesis of cis-[ 18F]4-fluoro-l-proline

AU - Behnam Azad, Babak

AU - Ashique, Rezwan

AU - Labiris, N. Renée

AU - Chirakal, Raman

PY - 2012/1

Y1 - 2012/1

N2 - 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 2m triflic acid at 145°C for 10min, or in two steps where the intermediate was heated in 1m HCl at 110°C for 10min followed by stirring at room temperature in 1 N NaOH for 5min. 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 C 18 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.

AB - 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 2m triflic acid at 145°C for 10min, or in two steps where the intermediate was heated in 1m HCl at 110°C for 10min followed by stirring at room temperature in 1 N NaOH for 5min. 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 C 18 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.

KW - fluorine-18

KW - fluoro- l -proline

KW - nucleophilic fluorination

KW - PET

KW - pulmonary fibrosis

KW - radiolabeling

UR - http://www.scopus.com/inward/record.url?scp=84856339759&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856339759&partnerID=8YFLogxK

U2 - 10.1002/jlcr.1947

DO - 10.1002/jlcr.1947

M3 - Article

AN - SCOPUS:84856339759

VL - 55

SP - 23

EP - 28

JO - Journal of Labelled Compounds and Radiopharmaceuticals

JF - Journal of Labelled Compounds and Radiopharmaceuticals

SN - 0362-4803

IS - 1

ER -