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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 Gln6residue 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 (Kd∼ 100 nM) increased 10-fold as compared to PSBP-0 (Kd∼ 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 (Kd∼ 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 mTc)-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 mTc)-PSBP-6 is a promising probe for noninvasive imaging of apoptotic cells. [ABSTRACT FROM AUTHOR]