title: A modular platform for the rapid site-specific radiolabeling of proteins with 18F exemplified by quantitative positron emission tomography of human epidermal growth factor receptor 2.
abstract: Receptor-specific proteins produced by genetic engineering are attractive as PET imaging agents, but labeling with conventional (18)F-based prosthetic groups is problematic due to long synthesis times, poor radiochemical yields, and low specific activities. Therefore, we developed a modular platform for the rapid preparation of water-soluble prosthetic groups capable of efficiently introducing (18)F into proteins. The utility of this platform is demonstrated by the thiol-specific prosthetic group, [(18)F]FPEGMA, which was used to produce site-specifically (18)F-labeled protein ((18)F-trastuzumab-ThioFab) in 82 min with a total radiochemical yield of 13 +/- 3% and a specific activity of 2.2 +/- 0.2 Ci/micromol. (18)F-trastuzumab-ThioFab retained the biological activity of native protein and was successfully validated in vivo with microPET imaging of Her2 expression in a xenograft tumor-bearing murine model modulated by the Hsp90 inhibitor, 17-(allylamino)-17-demethoxygeldanamycin.
authors.affiliation: Department of Biomedical Imaging, Genentech Inc., South San Francisco, California 94080, USA.
authors.forename: Herman S
authors.initials: HS
authors.lastname: Gill
authors.forename: Jeff N
authors.initials: JN
authors.lastname: Tinianow
authors.forename: Annie
authors.initials: A
authors.lastname: Ogasawara
authors.forename: Judith E
authors.initials: JE
authors.lastname: Flores
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Vanderbilt
authors.forename: Helga
authors.initials: H
authors.lastname: Raab
authors.forename: Justin M
authors.initials: JM
authors.lastname: Scheer
authors.forename: Richard
authors.initials: R
authors.lastname: Vandlen
authors.forename: Simon-P
authors.initials: SP
authors.lastname: Williams
authors.forename: Jan
authors.initials: J
authors.lastname: Marik
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016227:Benzoquinones; D066246:ErbB Receptors / Q000032:analysis*; D005462:Fluorine Radioisotopes; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007553:Isotope Labeling / Q000379:methods*; D047029:Lactams, Macrocyclic; D051379:Mice; D009374:Neoplasms, Experimental / Q000175:diagnosis; D049268:Positron-Emission Tomography / Q000379:methods*; D015202:Protein Engineering; D011506:Proteins / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D014183:Transplantation, Heterologous; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D016227:Benzoquinones; D066246:ErbB Receptors; D005462:Fluorine Radioisotopes; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011506:Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C112765:tanespimycin