title: A binding-site barrier affects imaging efficiency of high affinity amyloid-reactive peptide radiotracers in vivo.
abstract: Amyloid is a complex pathology associated with a growing number of diseases including Alzheimer's disease, type 2 diabetes, rheumatoid arthritis, and myeloma. The distribution and extent of amyloid deposition in body organs establishes the prognosis and can define treatment options; therefore, determining the amyloid load by using non-invasive molecular imaging is clinically important. We have identified a heparin-binding peptide designated p5 that, when radioiodinated, was capable of selectively imaging systemic visceral AA amyloidosis in a murine model of the disease. The p5 peptide was posited to bind effectively to amyloid deposits, relative to similarly charged polybasic heparin-reactive peptides, because it adopted a polar α helix secondary structure. We have now synthesized a variant, p5R, in which the 8 lysine amino acids of p5 have been replaced with arginine residues predisposing the peptide toward the α helical conformation in an effort to enhance the reactivity of the peptide with the amyloid substrate. The p5R peptide had higher affinity for amyloid and visualized AA amyloid in mice by using SPECT/CT imaging; however, the microdistribution, as evidenced in micro-autoradiographs, was dramatically altered relative to the p5 peptide due to its increased affinity and a resultant "binding site barrier" effect. These data suggest that radioiodinated peptide p5R may be optimal for the in vivo detection of discreet, perivascular amyloid, as found in the brain and pancreatic vasculature, by using molecular imaging techniques; however, peptide p5, due to its increased penetration, may yield more quantitative imaging of expansive tissue amyloid deposits.
authors.affiliation: Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, USA. jwall@utmck.edu
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Wall
authors.forename: Angela
authors.initials: A
authors.lastname: Williams
authors.forename: Tina
authors.initials: T
authors.lastname: Richey
authors.forename: Alan
authors.initials: A
authors.lastname: Stuckey
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Craig
authors.initials: C
authors.lastname: Wooliver
authors.forename: Sallie
authors.initials: S
authors.lastname: Macy
authors.forename: Eric
authors.initials: E
authors.lastname: Heidel
authors.forename: Neil
authors.initials: N
authors.lastname: Gupta
authors.forename: Angela
authors.initials: A
authors.lastname: Lee
authors.forename: Brianna
authors.initials: B
authors.lastname: Rader
authors.forename: Emily B
authors.initials: EB
authors.lastname: Martin
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kennel
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D006493:Heparin / Q000737:chemistry / Q000378:metabolism; D055767:Immobilized Proteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D057054:Molecular Imaging / Q000379:methods*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011849:Radioactive Tracers; D013154:Spleen / Q000000981:diagnostic imaging / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
chemical_list: D000682:Amyloid; D055767:Immobilized Proteins; D010455:Peptides; D011849:Radioactive Tracers; D006493:Heparin