Imaging TNFR1 And Integrin ?_v?₃ Positive Breast Carcinoma With A Novel Flurine-18 Labeled Heterodimer Peptide Probe

Chapter 1 Imaging TNFR1 Positive breast carcinoma with a Novel Flurine-18 Labeled Peptide ProbePurpose:We have screened a novel ligand targeting TNFR1 which named WH701 by using technology of phage-displayed peptide libraries.WH701 conjugated by NOTA-NHS.NOTA-WH701 was radiolabeled with 18F using NOTA-AlF chelation reaction.After this,we evaluated the diagnostic property of[18F]AlF-NOTA-WH701 in vitro and in vivo.Procedures:The peptide was radiolabeled by reacting the fluorine-18 fluoride-aluminum complex with the cyclic chelator,1,4,7-triazacyclononane-1,4,7-triacetic acid(NOTA).The tumor-targeting efficacy and receptor-binding characteristics of[18F]AlF-NOTA-WH701 were tested in vitro and in vivo.Results:WH701 exhibited moderate affinity towards TNFR1 in vitro.[18F]AlF-NOTA-WH701 demonstrated significantly tumor uptake in vivo.The uptake of[18F]AlF-NOTA-WH701 by an MCF-7 breast carcinoma was inhibited distinctly in the presence of unlabeled WH701,[18F]AlF-NOTA-WH701 showed a favorite imaging quality.Conclusions:[18F]AlF-NOTA-WH701 displayed a moderate receptor-targeting property both in vitro and in vivo.But its affinity to TNFR1 can still be improved by chemical modifications.Chapter 2 Imaging TNFR1 and Integrin ?v?3 Positive Breast Carcinoma with a Novel Flurine-18 labeled Heterodimer peptide probeObjects:Radiolabeled WH701 and Arg-Gly-Asp(RGD)peptide have received interests for their capacity to serve as radiopharmaceuticals for imaging TNFR1 and integrin ?v?3 positive tumors respectively.We synthesized a RGD-WH701 heterodimeric peptide which consisted of RGD and WH701 motifs in one integrate probe.This study aimed to investigate the dual receptor-targeting property and tumor diagnostic value of fluorine-18 labeled RGD-WH701 heterodimeric peptide.Methods:A RGD-WH701 heterodimer peptide was synthesized from WH701 and c(RGDyK)through a glutamate and two polyethylene glycol linker as well as three glycine.The peptide was radiolabeled by reacting the fluorine-18 fluoride-aluminum complex with the cyclic chelator,1,4,7-triazacyclononane-1,4,7-triacetic acid(NOTA).The tumor-targeting efficacy and receptor-binding characteristics of[18F]AlF-NOTA-Gly3-E(2PEG4-RGD-WH701)were tested in vivo preliminarily.Results:[18F]AlF-NOTA-Gly3-E(2PEG4-RGD-WH701)exhibited significantly higher tumor uptake than[18F]AlF-NOTA-RGD and[18F]AlF-NOTA-WH701 in vivo.The uptake of fluorine-18 labeled heterodimer by an MCF-7 breast carcinoma tumor was inhibited only partially in the presence of an unlabeled RGD or WH701 but was blocked completely in the presence of both RGD and WH701.[18F]AlF-NOTA-Gly3-E(2PEG4-RGD-WH701)showed improved in vivo pharmacokinetics,resulting in a more preferable imaging quality compared with the monomeric RGD and WH701 peptides.Conclusion:[18F]AlF-NOTA-Gly3-E(2PEG4-RGD-WH701)displayed significantly improved receptor-targeting properties compared with the fluorine-18 labeled RGD or WH701 monomers in vivo.These synergistic effects of the RGD-WH701 heterodimer provide a foundation for its further applicability investigations in clinical tumor imaging.