Rapid solid phase synthesis and biodistribution of 18F-labelled linear peptides

Julie Sutcliffe, Michael J. O'Doherty, Paul K. Marsden, Ian R. Hart, John F. Marshall, Sukvinder S. Bansal

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

A rapid method for radiolabelling short peptides with 18F (t1/2=109.7 min) for use in positron emission tomography (PET) was developed. Linear peptides (13mers) were synthesised using solid phase peptide synthesis and 9-fluorenylmethoxycarbonyl (Fmoc) chemistry. The peptides were assembled on a solid-phase polyethylene glycol-polystyrene support using the "hyper acid labile" linker xanthen-2-oxyvaleric acid and were labelled in situ with 4-[19F]- or 4-[18F]fluorobenzoic acid. Optimum coupling of 4-[19F]fluorobenzoic acid to the peptidyl resin was achieved within 2 min using N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]- Nmethylmethanaminium hexafluorophosphate N-oxide (HATU/DIPEA), and optimum cleavage was achieved within 7 min using trifluoroacetic acid/phenol/water/Triisopropylsilane at 37°C. The linear peptides were rapidly labelled with 4-[18F]fluorobenzoic acid with an overall radiochemical yield of 80%-90% (decay corrected), a radiochemical purity of >95% without HPLC purification and an overall synthesis time of 20 min. This novel method was used to label peptides containing the arginine-glycine-aspartic acid (RGD) motif, the binding site of many integrins. In vitro studies showed that the fluorobenzoyl prosthetic group had no deleterious effect on the ability of these peptides to inhibit the binding of human cells via integrins. Biodistribution studies in tumour-bearing mice showed that although the linear peptides were rapidly removed from the circulation by the liver and kidneys, there was a transient and non-RGD-dependent accumulation in the tumour of both the test and the control peptides. The use of more selective peptides with a longer half-life in the circulation combined with this rapid labelling technique will significantly enhance the application of peptides in PET.

Original languageEnglish (US)
Pages (from-to)754-759
Number of pages6
JournalEuropean Journal Of Nuclear Medicine
Volume29
Issue number6
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Solid-Phase Synthesis Techniques
Peptides
Integrins
Positron-Emission Tomography
Liver Circulation
Trifluoroacetic Acid
Acids
Renal Circulation
Phenol
Aspartic Acid
Glycine
Oxides
Half-Life
Arginine
Neoplasms
Binding Sites
High Pressure Liquid Chromatography

Keywords

  • Fluorine-18
  • Positron emission tomography
  • Solid phase peptide synthesis

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology

Cite this

Rapid solid phase synthesis and biodistribution of 18F-labelled linear peptides. / Sutcliffe, Julie; O'Doherty, Michael J.; Marsden, Paul K.; Hart, Ian R.; Marshall, John F.; Bansal, Sukvinder S.

In: European Journal Of Nuclear Medicine, Vol. 29, No. 6, 2002, p. 754-759.

Research output: Contribution to journalArticle

Sutcliffe, Julie ; O'Doherty, Michael J. ; Marsden, Paul K. ; Hart, Ian R. ; Marshall, John F. ; Bansal, Sukvinder S. / Rapid solid phase synthesis and biodistribution of 18F-labelled linear peptides. In: European Journal Of Nuclear Medicine. 2002 ; Vol. 29, No. 6. pp. 754-759.
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AU - Marshall, John F.

AU - Bansal, Sukvinder S.

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AB - A rapid method for radiolabelling short peptides with 18F (t1/2=109.7 min) for use in positron emission tomography (PET) was developed. Linear peptides (13mers) were synthesised using solid phase peptide synthesis and 9-fluorenylmethoxycarbonyl (Fmoc) chemistry. The peptides were assembled on a solid-phase polyethylene glycol-polystyrene support using the "hyper acid labile" linker xanthen-2-oxyvaleric acid and were labelled in situ with 4-[19F]- or 4-[18F]fluorobenzoic acid. Optimum coupling of 4-[19F]fluorobenzoic acid to the peptidyl resin was achieved within 2 min using N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]- Nmethylmethanaminium hexafluorophosphate N-oxide (HATU/DIPEA), and optimum cleavage was achieved within 7 min using trifluoroacetic acid/phenol/water/Triisopropylsilane at 37°C. The linear peptides were rapidly labelled with 4-[18F]fluorobenzoic acid with an overall radiochemical yield of 80%-90% (decay corrected), a radiochemical purity of >95% without HPLC purification and an overall synthesis time of 20 min. This novel method was used to label peptides containing the arginine-glycine-aspartic acid (RGD) motif, the binding site of many integrins. In vitro studies showed that the fluorobenzoyl prosthetic group had no deleterious effect on the ability of these peptides to inhibit the binding of human cells via integrins. Biodistribution studies in tumour-bearing mice showed that although the linear peptides were rapidly removed from the circulation by the liver and kidneys, there was a transient and non-RGD-dependent accumulation in the tumour of both the test and the control peptides. The use of more selective peptides with a longer half-life in the circulation combined with this rapid labelling technique will significantly enhance the application of peptides in PET.

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