C - Chemistry – Metallurgy – 07 – K
Patent
C - Chemistry, Metallurgy
07
K
C07K 7/02 (2006.01) A61K 51/08 (2006.01) C07K 1/13 (2006.01) C07K 4/00 (2006.01) C07K 7/06 (2006.01)
Patent
CA 2266233
1. Several hundred Rhenium (Re)-peptide libraries produced by combinatorial chemistry were screened to identify a potential high-affinity Tc-99m formyl-peptide receptor (FPR) antagonist or partial agonist radiopharmaceutical ideal for efficiently imaging sites of inflammation and infection. 2. Functional assays with various N-terminal capping group modifications identified several novel peptides which significantly stimulated or inhibited the release of myeloperoxidase (MPO) from elicited rat neutrophils ~ formyl-methionyl-leucyl-phenylalanine (fMLF) (p < 0.05). 3. Corresponding Re-complexed libraries exhibited varied binding affinity to the FPR receptor with several libraries exhibiting significant displacement of the 3H-fMLF. 4. In particular, competition binding of library ReORP553-17 significantly inhibited 3H-fMLF binding in a dose-dependent manner by 47.6 % and 91.4% when administered at lµM and 10 µM respectively. 5. Deconvolution compounds from Re-library RP553 17 exhibited IC50 values ranging from 0.73 (0.60 to 0.88) µM to 5.93 (2.96 to 11.91) µM in elicited rat neutrophils (r ~ 0.98). Deconvolution compound ReORP553 17-01 exhibited the greatest affinity binding to elicited rat neutrophils with a IC50 value of 0.73 (0.60 to 0.88) µM which was approximately 12-fold heater in affinity than known antagonist N-t-BocMLF in the present study (n=3; r = 0.99). 6. Competition binding of ReORP553 17-01 to human neutrophils indicated an IC50 value of 0.14 (0.008 to 2.4) µM (n=1; r =0.97) which was comparable to the IC50 value of 0.175 (0.03 to 1.04)µM for N-t-BocMLF. 7. MPO release was significantly reduced by 10µM ReORP553 17-01 (n=1) in cells stimulated with fMLF and release was not increased in PMNs lacking fMLF stimulation at this concentration (p < 0.05). Further studies indicate that ReORP553 17-01 antagonizes the release of intracellular Ca2+ in fMLF-stimulated neutrophils but causes increases in cells lacking fMLF stimulation at concentrations between 1.0µM to 10µM. This indicates partial agonist function. 8. HPLC analysis of the radiolabelling of RP553 17-01 with Na[99Tc04] indicated that the product 99mTc-RP553 17-01 had a radiochemical purity >90%. 9. This Re-based combinatorial approach identified several compounds that have potential as new Tc-99m-labelled FPR ligands which can be used for rapid identification of sites of inflammation or infection. In particular, the inhibitory function of ReORP553 17-01 on MPO release and rises in intracellular Ca2+ indicate that it may serve as an effective diagnostic agent without causing host tissue damage.
Lawrence Betty Chee-Lon
Pollak Alfred
Pollock Catherine Michelle
Ribic Christine Maria
Roe David
Deeth Williams Wall Llp
Lawrence Betty Chee-Lon
Pollak Alfred
Pollock Catherine Michelle
Resolution Pharmaceuticals Inc.
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