Peptide-based imaging agents targeting phosphatidylserine for the detection of apoptosis

J Med Chem. 2011 Mar 24;54(6):1825-35. doi: 10.1021/jm101477d. Epub 2011 Feb 24.

Abstract

A 14-residue phosphatidylserine (PS)-binding peptide FNFRLKAGQKIRFG (PSBP-0) was scanned with Ala. In addition, a radiometal chelator (SAAC) was introduced at selected sites of the lead peptides. Substitution of the Gln(6) residue in PSBP-0 with Ala resulted in a significant increase in binding affinity to PS as determined by surface plasmon resonance sensorgrams. The binding affinity of the resulting peptide FNFRLKAGAKIRFG (PSBP-6, molecular mass = 1623 Da) to PS (K(d) ∼ 100 nM) increased 10-fold as compared to PSBP-0 (K(d) ∼ 1.38 μM). Introduction of SAAC-Re to the N terminus of PSBP-6 further increased the binding affinity of the resulting peptide SAAC(Re)-PSBP-6 (K(d) ∼ 26 nM). SAAC(Re)-PSBP-6 shows specific binding to apoptotic cells in cell-based assays. Biodistribution studies showed significantly higher uptake of SAAC((99 m)Tc)-PSBP-6 in B16/F10 melanoma treated with poly(L-glutamic acid)-paclitaxel than untreated tumors (4.06 ± 0.55% ID/g vs 1.61 ± 0.33% ID/g, P = 0.00011). SAAC((99 m)Tc)-PSBP-6 is a promising probe for noninvasive imaging of apoptotic cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Line, Tumor
  • Chelating Agents / chemical synthesis
  • Chelating Agents / chemistry
  • Coordination Complexes / chemical synthesis*
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacokinetics
  • Humans
  • Lysine / analogs & derivatives
  • Lysine / chemical synthesis
  • Lysine / chemistry
  • Melanoma, Experimental / diagnostic imaging
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacokinetics
  • Phosphatidylserines / metabolism*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Radioisotopes
  • Radionuclide Imaging
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Rhenium*
  • Technetium*
  • Tissue Distribution
  • Transplantation, Heterologous

Substances

  • Chelating Agents
  • Coordination Complexes
  • Oligopeptides
  • Phosphatidylserines
  • Pyridines
  • Radioisotopes
  • Radiopharmaceuticals
  • Rhenium
  • Technetium
  • Lysine