PET Imaging of Extracellular pH in Tumors with 64Cu- and 18F-Labeled pHLIP Peptides: A Structure—Activity Optimization Study

Dustin Wayne Demoin, Linden C Wyatt, Kimberly J Edwards, Dalya Abdel-Atti, Mirkka Sarparanta, Jacob Pourat, Valerie A Longo, Sean D Carlin, Donald M Engelman, Oleg A Andreev, Yana K Reshetnyak, Nerissa Viola-Villegas, Jason S Lewis

Research output: Contribution to journalArticleScientificpeer-review


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 (Cu-64 and F-18) 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 Cu-64 or [F-18]-AIF 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 18F (4T1 uptake; 8.9 +/- 1.7%ID/g at 4 h p.i.) or Cu-64 (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 F-18- or Cu-64-labeled NO2A-cysVar3.
Original languageEnglish
JournalBioconjugate Chemistry
Issue number9
Pages (from-to)2014-2023
Number of pages10
Publication statusPublished - 9 Jul 2016
Externally publishedYes
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3111 Biomedicine
  • 116 Chemical sciences

Cite this