Synthesis and screening of a library of Re/Tc-based amyloid probes derived from beta-breaker peptides.
Through the development and application of a unique approach for producing Re-metallopeptides, a new class of peptide-derived probes that are designed to target beta-amyloid plaques was developed. Derivatives of a class of beta-breaker peptides having the core sequence lvffa or affvl (lower case letters represent D-amino acids) and the single amino acid chelate quinoline (SAACQ) ligand which can bind Re and (99m)Tc were prepared on an automated peptide synthesizer. Both monomeric and dimeric peptides were synthesized in modest to good yields where in select examples a biotin-containing amino acid derivative was included to act as a linker point for further conjugation to carrier proteins. The Re complexes for all reported peptides were prepared similarly and screened for their ability to inhibit fibrillogenesis. Two of the reported compounds showed excellent inhibitory properties (8a: 40 +/- 5% amyloid formation versus control; 16: 40 +/- 4%) and warrant further investigation. For one of these leads, the (99m)Tc analogue was synthesized and the product showed high stability toward histidine and cysteine challenges, making it a viable candidate for in vivo biodistribution studies.
Stephenson
Karin A
KA
Department of Chemistry, McMaster University, Hamilton, ON, Canada.
Reid
Leslie C
LC
Zubieta
Jon
J
Babich
John W
JW
Kung
Mei-Ping
MP
Kung
Hank F
HF
Valliant
John F
JF
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D007553:Isotope Labeling; D008024:Ligands; D008667:Metalloproteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D008968:Molecular Conformation; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D009842:Oligopeptides / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects*; D019151:Peptide Library; D012211:Rhenium / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013667:Technetium / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D008024:Ligands; D008667:Metalloproteins; D015335:Molecular Probes; D009842:Oligopeptides; D010446:Peptide Fragments; D019151:Peptide Library; C078592:amyloid beta-protein (1-40); D012211:Rhenium; D013667:Technetium