title: PET Imaging of Extracellular pH in Tumors with (64)Cu- and (18)F-Labeled pHLIP Peptides: A Structure-Activity Optimization Study.
abstract: pH (low) insertion peptides (pHLIP peptides) target acidic extracellular environments in vivo due to pH-dependent cellular membrane insertion. Two variants (Var3 and Var7) and wild-type (WT) pHLIP peptides have shown promise for in vivo imaging of breast cancer. Two positron emitting radionuclides ((64)Cu and (18)F) were used to label the NOTA- and NO2A-derivatized Var3, Var7, and WT peptides for in vivo biodistribution studies in 4T1 orthotopic tumor-bearing BALB/c mice. All of the constructs were radiolabeled with (64)Cu or [(18)F]-AlF in good yield. The in vivo biodistribution of the 12 constructs in 4T1 orthotopic allografted female BALB/c mice indicated that NO2A-cysVar3, radiolabeled with either (18)F (4T1 uptake; 8.9 ± 1.7%ID/g at 4 h p.i.) or (64)Cu (4T1 uptake; 8.2 ± 0.9%ID/g at 4 h p.i. and 19.2 ± 1.8% ID/g at 24 h p.i.), shows the most promise for clinical translation. Additional studies to investigate other tumor models (melanoma, prostate, and brain tumor models) indicated the universality of tumor targeting of these tracers. From this study, future clinical translation will focus on (18)F- or (64)Cu-labeled NO2A-cysVar3.
authors.forename: Dustin Wayne
authors.initials: DW
authors.lastname: Demoin
authors.affiliation: Physics Department, University of Rhode Island , 2 Lippitt Road, Kingston, Rhode Island 02881, United States.
authors.forename: Linden C
authors.initials: LC
authors.lastname: Wyatt
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Edwards
authors.forename: Dalya
authors.initials: D
authors.lastname: Abdel-Atti
authors.forename: Mirkka
authors.initials: M
authors.lastname: Sarparanta
authors.forename: Jacob
authors.initials: J
authors.lastname: Pourat
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Longo
authors.forename: Sean D
authors.initials: SD
authors.lastname: Carlin
authors.affiliation: pHLIP, Inc , 2 Lippitt Road, Kingston, Rhode Island 02881, United States.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Engelman
authors.affiliation: Physics Department, University of Rhode Island , 2 Lippitt Road, Kingston, Rhode Island 02881, United States.|pHLIP, Inc , 2 Lippitt Road, Kingston, Rhode Island 02881, United States.
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Andreev
authors.affiliation: Physics Department, University of Rhode Island , 2 Lippitt Road, Kingston, Rhode Island 02881, United States.|pHLIP, Inc , 2 Lippitt Road, Kingston, Rhode Island 02881, United States.
authors.forename: Yana K
authors.initials: YK
authors.lastname: Reshetnyak
authors.affiliation: Department of Oncology, Karmanos Cancer Institute , Detroit, Michigan 48201, United States.
authors.forename: Nerissa
authors.initials: N
authors.lastname: Viola-Villegas
authors.affiliation: Weill Cornell Medical College , 1300 York Avenue, New York, New York 10065, United States.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes; D005110:Extracellular Space / Q000737:chemistry*; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D003301:Copper Radioisotopes; D005462:Fluorine Radioisotopes; D008565:Membrane Proteins; D011849:Radioactive Tracers; C533201:pHLIP protein