peptides as molecular imaging probes

8/8/2019 Peptides as Molecular Imaging Probes

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1.0 Peptides as molecular imaging probes

Molecular imaging is a rapidly emerging biomedical research in diagnostics and therapeuticfields due to current indispensable tools in modern diagnostics [1]. Thus the need for highly sensitive andspecific molecular imaging probes is still unmet. In order to design diagnostic imaging andradiotherapeutic agents, a high target/background ratio, target uptake and rapid removal of untargeted

drug is desirable. Proteins, antibodies and their fragment are perfect candidates due to high specificityaffinity and selectivity to the target organs. With the advancement of combinatorial chemistry andphage display methods, peptides are currently receiving considerable attention as molecular imagingprobes. In addition, peptides have distinct advantages over proteins and antibodies due to manyappealing characteristics:

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Rapid clearance in the body ensures the radioisotopes are not retained in the body for aprolonged period of time.

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Have low toxicity and immunogenicity3.

They can easily be synthesized, modified to optimize their binding affinity and improve theirstability against proteolytic degradation and in vivo circulation

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With the well established peptide synthesis protocols they are easy to scale up and reproducePhage display is a powerful technique that allows vast sequence space screening, providing a

means to improve peptide affinity and generate unique peptides that binds any given target [1]. Due tothe diversified methods of peptide synthesis, peptides can be directly or indirectly labeled with imagingprobes to provide or augment the imaging signals, depending on the modality. For example, severalradioisotopes ( 99m Tc, 18F, 64Cu, 111 In, 123 I, 68Ga) for PET and SPECT, organic near-infrared (NIR)fluorophores or quantum dots (QDs) for optical imaging and magnetic nanoparticles for MRI can beconjugated to peptides via organic linkers, macrocyclic or branched chelators (figure 1), polymers ornanoplatforms [2].

Several classic examples of peptides have been utilized as imaging agents for peptide-receptorinteraction due to their high selectivity and affinity to their cognitive receptors as described below.

1.1 Somatostatin Analogs Somatostatins (SST) are regulatory hormones with inhibitory effects on secretion of growthhormone, insulin, glucagon, gastrin, cholecystokinin, vasoactive intestinal peptide (VIP) and secretin [3].These cyclopeptides are mainly produced by endocrine, gastrointestinal, immune and neuronal cells aswell as by certain tumours [3]. Radionuclide labeled synthetic somatostatin analogs like octreotide havelong been investigated for imaging neuroendocrine tumors due to their enhanced metabolic stabilityand biological activity compared to the native hormone.111 In-DTPA, 68GA-DOTA, 64Cu-DOTA and 18F-FP-Gluc-labeled SST analogues have been developed forimaging various tumors [2].

1.2 a vb 3-Integrin Analogsa vb 3 integrins are closely related with tumor progression and plays an important role during

tumor angiogenesis and formation of new blood vessels. Integrin peptides contain an Arg-Gly-Asp (RGD)motif. a vb 3 integrin has received considerable attention in diagnostic cancer imaging due to itsoverexpression in several forms of tumors including melanomas, ovarian and lung carcinoma,neuroblastomas, glioblastomas and breast cancer [2]. Of particular interest, 18F labeled cyclo(Arg-Gly-Asp-D-Tyr-Lys) analog has been used to identify a vb 3 receptor expression in patients with melanoma,sarcoma, breast cancer and glioblastoma [4].



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Other peptides like neurotensin (NT), a neurotransmitter is being investigated for ductalpancreatic adenocarcinomas which overexpressed NT receptors. Radiolabeled glucagon-like peptide-1(GLP-1) and Exendin-4 have been developed to target insulinomas which overexpress the GLP-1receptors.

All these peptides require custom design to improve their metabolic stability and half life in vivo.BIOSYNTHESIS, INC. a leading manufacturer of custom peptides in small scale research and bulk is nowoffering peptide conjugates containing metal chelators like DOTA, NOTA, TETA and DTPA.References:[1] S. L. Deutscher, Chem Rev 2010 , 110 , 3196-3211.[2] S. Lee, J. Xie and X. Chen, Chem Rev 2010 , 110 , 3087-3111.[3] G. Weckbecker, I. Lewis, R. Albert, H. A. Schmid, D. Hoyer and C. Bruns, Nat Rev Drug Discov 2003 , 2 ,999-1017.[4] a) A. J. Beer, A. L. Grosu, J. Carlsen, A. Kolk, M. Sarbia, I. Stangier, P. Watzlowik, H. J. Wester, R.Haubner and M. Schwaiger, Clin Cancer Res 2007 , 13 , 6610-6616; b) A. J. Beer, M. Niemeyer, J. Carlsen,M. Sarbia, J. Nahrig, P. Watzlowik, H. J. Wester, N. Harbeck and M. Schwaiger, J Nucl Med 2008 , 49 , 255-259.[5] J. C. Reubi, J. C. Schaer and B. Waser, Cancer Res 1997 , 57 , 1377-1386.[6] J. C. Reubi and B. Waser, Int J Cancer 1996 , 67 , 644-647.[7] J. B. Tatro, Z. Wen, M. L. Entwistle, M. B. Atkins, T. J. Smith, S. Reichlin and J. R. Murphy, Cancer Res1992 , 52 , 2545-2548.[8] Y. Miao, F. Gallazzi, H. Guo and T. P. Quinn, Bioconjug Chem 2008 , 19 , 539-547.[9] J. Yang, H. Guo, F. Gallazzi, M. Berwick, R. S. Padilla and Y. Miao, Bioconjug Chem 2009 , 20 , 1634-1642.

peptides as molecular imaging probes

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