A new strategy for the preparation of peptide-targeted technetium and rhenium radiopharmaceuticals. The automated solid-phase synthesis, characterization, labeling, and screening of a peptide-ligand library targeted at the formyl peptide receptor.
A new solid-phase synthetic methodology was developed that enables libraries of peptide-based Tc(I)/Re(I) radiopharmaceuticals to be prepared using a conventional automated peptide synthesizer. Through the use of a tridentate ligand derived from N-alpha-Fmoc-l-lysine, which we refer to as a single amino acid chelate (SAAC), a series of 12 novel bioconjugates [R-NH(CO)ZLF(SAAC)G, R = ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, benzyl; Z = Met, Nle] that are designed to target the formyl peptide receptor (FPR) were prepared. Construction of the library was carried out in a multiwell format on an Advanced ChemTech 348 peptide synthesizer where multi-milligram quantities of each peptide were isolated in high purity without HPLC purification. After characterization, the library components were screened for their affinity for the FPR receptor using flow cytometry where the K(d) values were found to be in the low micromolar range (0.5-3.0 microM). Compound 5j was subsequently labeled with (99m)Tc(I) and the product isolated in high radiochemical yield using a simple Sep-Pak purification procedure. The retention time of the labeled compound matched that of the fully characterized Re-analogue which was prepared through the use of the same solid-phase synthesis methodology that was used to construct the library. The work reported here is a rare example of a method by which libraries of peptide-ligand conjugates and their rhenium complexes can be prepared.
Stephenson
Karin A
KA
Department of Chemistry, McMaster University, Hamilton, ON, Canada L8S 4M1.
Banerjee
Sangeeta Ray
SR
Sogbein
Oyebola O
OO
Levadala
Murali K
MK
McFarlane
Nicole
N
Boreham
Douglas R
DR
Maresca
Kevin P
KP
Babich
John W
JW
Zubieta
Jon
J
Valliant
John F
JF
D001331:Automation; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D019151:Peptide Library; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D012211:Rhenium / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013379:Substrate Specificity; D013667:Technetium / Q000737:chemistry*
D008024:Ligands; D010446:Peptide Fragments; D019151:Peptide Library; D019275:Radiopharmaceuticals; D044042:Receptors, Formyl Peptide; D012211:Rhenium; D013667:Technetium