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[18F]-SuPAR: A Radiofluorinated Probe for Noninvasive Imaging of DNA Damage-Dependent Poly(ADP-ribose) Polymerase Activity

Research output: Contribution to journalArticle

Adam J Shuhendler, Lina Cui, Zixin Chen, Bin Shen, Min Chen, Michelle L James, Timothy H Witney, Magdalena Bazalova-Carter, Sanjiv S Gambhir, Frederick T Chin, Edward E Graves, Jianghong Rao

Original languageEnglish
Pages (from-to)1331-1342
Number of pages12
JournalBioconjugate Chemistry
Volume30
Issue number5
Early online date11 Apr 2019
DOIs
Accepted/In press9 Apr 2019
E-pub ahead of print11 Apr 2019
Published15 May 2019

King's Authors

Abstract

Poly(ADP ribose) polymerase (PARP) enzymes generate poly(ADP ribose) post-translational modifications on target proteins for an array of functions centering on DNA and cell stress. PARP isoforms 1 and 2 are critically charged with the surveillance of DNA integrity and are the first line guardians of the genome against DNA breaks. Here we present a novel probe ([18F]-SuPAR) for noninvasive imaging of PARP-1/2 activity using positron emission tomography (PET). [18F]-SuPAR is a radiofluorinated nicotinamide adenine dinucleotide (NAD) analog that can be recognized by PARP-1/2 and incorporated into the long branched polymers of poly(ADP ribose) (PAR). The measurement of PARP-1/2 activity was supported by a reduction of radiotracer uptake in vivo following PARP-1/2 inhibition with talazoparib treatment, a potent PARP inhibitor recently approved by FDA for treatment of breast cancer, as well as ex vivo colocalization of radiotracer analog and poly(ADP ribose). With [18F]-SuPAR, we were able to map the dose- and time-dependent activation of PARP-1/2 following radiation therapy in breast and cervical cancer xenograft mouse models. Tumor response to therapy was determined by [18F]-SuPAR PET within 8 h of administration of a single dose of radiation equivalent to one round of stereotactic ablative radiotherapy.

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