title: In vitro and in vivo evaluation of a novel 99mTc(CO)3-pyrazolyl conjugate of cyclo-(Arg-Gly-Asp-d-Tyr-Lys).
abstract: Radiolabeled peptides containing the Arg-Gly-Asp amino acid sequence (single letter code = RGD) have been studied extensively to target integrin receptors upregulated on tumor cells and neovasculature. Integrins are cell surface transmembrane glycoproteins that exist as alphabeta heterodimers. The alphavbeta3 integrin is known to be overexpressed in many tumor types and is expressed at lower levels in normal tissues. Furthermore, alphavbeta3 and alphavbeta5 subtypes are expressed in neovasculature during angiogenesis. Thus, there is some impetus to image angiogenesis and tumor formation in vivo using RGD-based peptide targeting vectors. In this study, we report the design and development of a new cyclic RGD analogue cyclo-[Arg-Gly-Asp-d-Tyr-Lys(PZ)] (PZ = 3,5-Me2-pz(CH2)2N((CH2)3COOH)(CH2)2NH2) that can be radiolabeled with the [99mTc(CO)3(H2O)3]+ metal aquaion. Radiochemical evaluation of this new conjugate in vitro indicated a facile radiosynthesis of the new 99mTc-RGD conjugate with high radiolabeling yields (>or=95%) and high specific activities. In vitro internalization and blocking assays in alphavbeta3 receptor-positive, human M21 melanoma cancer cells showed the ability of this conjugate to target the integrin receptor with high specificity and selectivity. In vivo pharmacokinetic studies in normal CF-1 mice showed rapid clearance from blood with excretion primarily via/through the renal-urinary system. In vivo accumulation of radioactivity in mice bearing either alphavbeta3 receptor-positive or negative human melanoma tumors showed receptor specific uptake of tracer with accumulations of 2.50 +/- 0.29 and 0.71 +/- 0.08% ID/g in alphavbeta3 integrin positive (M21) and negative (M21L) tumors at 1 h postinjection (p.i.), respectively.
authors: Department of Radiology, Department of Internal Medicine, and The Radiopharmaceutical Sciences Institute, University of Missouri-Columbia School of Medicine, Columbia, Missouri 65211, USA.
authors: Susana
authors: S
authors: Alves
authors: João D G
authors: JD
authors: Correia
authors: Lurdes
authors: L
authors: Gano
authors: Tammy L
authors: TL
authors: Rold
authors: Adam
authors: A
authors: Prasanphanich
authors: Roland
authors: R
authors: Haubner
authors: Marco
authors: M
authors: Rupprich
authors: Roger
authors: R
authors: Alberto
authors: Clemens
authors: C
authors: Decristoforo
authors: Isabel
authors: I
authors: Santos
authors: Charles J
authors: CJ
authors: Smith
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008546:Melanoma, Experimental / Q000000981:diagnostic imaging* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000378:metabolism*; D011720:Pyrazoles / Q000737:chemistry*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000378:metabolism*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D015609:Organotechnetium Compounds; D010456:Peptides, Cyclic; D011720:Pyrazoles; D019275:Radiopharmaceuticals; C047981:arginyl-glycyl-aspartic acid