title: Triazine-based tool box for developing peptidic PET imaging probes: syntheses, microfluidic radiolabeling, and structure-activity evaluation.
abstract: This study was aimed at developing a triazine-based modular platform for targeted PET imaging. We synthesized mono- or bis-cyclo(RGDfK) linked triazine-based conjugates specifically targeting integrin αvβ3 receptors. The core molecules could be easily linked to targeting peptide and radiolabeled bifunctional chelator. The spacer core molecule was synthesized in 2 or 3 steps in 64-80% yield, and the following conjugation reactions with cyclo(RGDfK) peptide or bifunctional chelator were accomplished using "click" chemistry or amidation reactions. The DOTA-TZ-Bis-cyclo(RGDfK) 13 conjugate was radiolabeled successfully with (64)Cu(OAc)2 using a microfluidic method, resulting in higher specific activity with above 95% labeling yields compared to conventional radiolabeling (SA ca. 850 vs 600 Ci/mmol). The dimeric cyclo(RGDfK) peptide was found to display significant bivalency effect using I(125)-Echistatin binding assay with IC50 value as 178.5 ± 57.1 nM, which displayed a 3.6-fold enhancement of binding affinity compared to DOTA-TZ-cyclo(RGDfK) 14 conjugate on U87MG human glioblastoma cell. Biodistribution of all four conjugates in female athymic nude mice were evaluated. DOTA-"Click"-cyclo(RGDfK) 15 had the highest tumor uptake among these four at 4 h p.i. with 1.90 ± 0.65%ID/g, while there was no clear bivalency effect for DOTA-TZ-BisRGD in vivo, which needs further experiments to address the unexpected questions.
authors.affiliation: Radiological Sciences Division, Mallinckrodt Institute of Radiology, Washington University School of Medicine , 510 South Kingshighway Boulevard, St. Louis, Missouri 63110, United States.
authors.forename: Hairong
authors.initials: H
authors.lastname: Li
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhou
authors.forename: Stephanie
authors.initials: S
authors.lastname: Krieger
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Parry
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Whittenberg
authors.forename: Amit V
authors.initials: AV
authors.lastname: Desai
authors.forename: Buck E
authors.initials: BE
authors.lastname: Rogers
authors.forename: Paul J A
authors.initials: PJ
authors.lastname: Kenis
authors.forename: David E
authors.initials: DE
authors.lastname: Reichert
mesh_terms: D000818:Animals; D057930:Click Chemistry; D003301:Copper Radioisotopes / Q000737:chemistry; D005260:Female; D005909:Glioblastoma / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling; D051379:Mice; D008819:Mice, Nude; D046210:Microfluidic Analytical Techniques; D057054:Molecular Imaging / Q000379:methods*; D015335:Molecular Probes / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D051381:Rats; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014227:Triazines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
chemical_list: D003301:Copper Radioisotopes; D039302:Integrin alphaVbeta3; D007457:Iodine Radioisotopes; D015335:Molecular Probes; D010456:Peptides, Cyclic; D014227:Triazines; C099250:cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl)