title: [18F]Galacto-RGD: synthesis, radiolabeling, metabolic stability, and radiation dose estimates.
abstract: It has been demonstrated in various murine tumor models that radiolabeled RGD-peptides can be used for noninvasive determination of alphavbeta3 integrin expression. Introduction of sugar moieties improved the pharmacokinetic properties of these peptides and led to tracer with good tumor-to-background ratios. Here we describe the synthesis, radiolabeling, and the metabolic stability of a glycosylated RGD-peptide ([18F]Galacto-RGD) and give first radiation dose estimates for this tracer. The peptide was assembled on a solid support using Fmoc-protocols and cyclized under high dilution conditions. It was conjugated with a sugar amino acid, which can be synthesized via a four-step synthesis starting from pentaacetyl-protected galactose. For radiolabeling of the glycopeptide, 4-nitrophenyl-2-[18F]fluoropropionate was used. This prosthetic group allowed synthesis of [18F]Galacto-RGD with a maximum decay-corrected radiochemical yield of up to 85% and radiochemical purity >98%. The overall radiochemical yield was 29 +/- 5% with a total reaction time including final HPLC preparation of 200 +/- 18 min. The metabolic stability of [18F]Galacto-RGD was determined in mouse blood and liver, kidney, and tumor homogenates 2 h after tracer injection. The average fraction of intact tracer in these organs was approximately 87%, 76%, 69%, and 87%, respectively, indicating high in vivo stability of the radiolabeled glycopeptide. The expected radiation dose to humans after injection of [18F]Galacto-RGD has been estimated on the basis of dynamic PET studies with New Zealand white rabbits. According to the residence times in these animals the effective dose was calculated using the MIRDOSE 3.0 program as 2.2 x 10(-2) mGy/MBq. In conclusion, [18F]Galacto-RGD can be synthesized in high radiochemical yields and radiochemical purity. Despite the time-consuming synthesis of the prosthetic group 185 MBq of [18F]Galacto-RGD, a sufficient dose for patient studies, can be produced starting with approximately 2.2 GBq of [18F]flouride. Moreover, the fast excretion, the suitable metabolic stability and the low estimated radiation dose allow to evaluate this tracer in human studies.
authors.affiliation: Department of Nuclear Medicine, Technische Universität München, 81675 München, Germany. R.Haubner@lrz.tum.de
authors.forename: Roland
authors.initials: R
authors.lastname: Haubner
authors.forename: Bertrand
authors.initials: B
authors.lastname: Kuhnast
authors.forename: Christian
authors.initials: C
authors.lastname: Mang
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Weber
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
mesh_terms: D000606:Amino Sugars / Q000737:chemistry; D000818:Animals; D001711:Biotransformation; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes; D005690:Galactose / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D006020:Glycopeptides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006801:Humans; D007202:Indicators and Reagents; D007553:Isotope Labeling; D013058:Mass Spectrometry; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011817:Rabbits; D011829:Radiation Dosage; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D014183:Transplantation, Heterologous
chemical_list: D000606:Amino Sugars; D005462:Fluorine Radioisotopes; D006020:Glycopeptides; D007202:Indicators and Reagents; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; C423503:fluorogalacto-RGD; D005690:Galactose