Iodinated benzimidazole PARP radiotracer for evaluating PARP1/2 expression in vitro and in vivo

Anderson, Redmond‐Craig; Makvandi, Mehran; Xu, Kuiying; Lieberman, Brian P.; Zeng, Chenbo; Pryma, Daniel A.; Mach, Robert H.

doi:10.1016/j.nucmedbio.2016.08.007

Cited by 28 publications

(24 citation statements)

References 39 publications

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“…125 I-KX1 (K i , ,8 nM) is structurally identical to 18 F-FTT except that 125 I replaces the fluoroethoxy moiety (36,37). It was shown in vitro that 125 I-KX1 correlated with PARP1 expression in a panel of breast and ovarian cancer cell lines but not with poly(adenosine diphosphate-ribose), as observed with 18 F-FTT.…”

Section: Radiolabeled Probes Structurally Similar To Rucaparibmentioning

confidence: 90%

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Molecular Imaging of PARP

2017

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The poly(adenosine diphosphate-ribose)polymerase (PARP) family of enzymes is an important factor in the cellular DNA damage response and has gained much attention for its role in many diseases, particularly cancer. Targeted molecular imaging of PARP using fluorescent or radiolabeled tags has followed on the success of therapeutic inhibitors and gained momentum over the past few years. This review covers PARP imaging from the very first imaging agents up to the current state of the technology, with a focus on the clinical applications made possible by these agents.

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Section: Radiolabeled Probes Structurally Similar To Rucaparibmentioning

confidence: 90%

“…Another study (37) presented 125 I-KX-02-019 (K i , 13.9 nM), a modified version of 125 I-KX1 that features a bicyclic instead of a tricyclic benzimidazole. 125 I-KX-02-019 is a close analog of AG14032 (38) (K i , 6.7 nM), another rucaparib predecessor, with its chloride replaced by 125 I.…”

Section: Radiolabeled Probes Structurally Similar To Rucaparibmentioning

confidence: 99%

Molecular Imaging of PARP

2017

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“…Several research groups have synthesized PARP-targeted radiotracers in the past; some of which were attached to radioiodine (14,(22)(23)(24). We showed that one of these tracers, 131 I-PARPi 14, has a high affinity with a concentration at which 50% of binding has been inhibited (IC 50 ) in the nanomolar range (11 6 3 nM) and a logP CHI of 2.3.…”

Section: Synthesis Specificity and In Vitro Performance Of 131 I-parpimentioning

confidence: 98%

PARP-1–Targeted Radiotherapy in Mouse Models of Glioblastoma

et al. 2018

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The DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is overexpressed in glioblastoma, with overall low expression in healthy brain tissue. Paired with the availability of specific small molecule inhibitors, PARP-1 is a near-ideal target to develop novel radiotherapeutics to induce DNA damage and apoptosis in cancer cells, while sparing healthy brain tissue. We synthesized anI-labeled PARP-1 therapeutic and investigated its pharmacology in vitro and in vivo. A subcutaneous tumor model was used to quantify retention times and therapeutic efficacy. A potential clinical scenario, intratumoral convection-enhanced delivery, was mimicked using an orthotopic glioblastoma model combined with an implanted osmotic pump system to study local administration of I-PARPi (PARPi is PARP inhibitor).I-PARPi is a 1(2H)-phthalazinone, similar in structure to the Food and Drug Administration-approved PARP inhibitor AZD-2281. In vitro studies have shown that I-PARPi and AZD-2281 share similar pharmacologic profiles.I-PARPi delivered 134.1 cGy/MBq intratumoral injected activity. Doses to nontarget tissues, including liver and kidney, were significantly lower. Radiation damage and cell death in treated tumors were shown by p53 activation in U87-MG cells transfected with a p53-bioluminescent reporter. Treated mice showed significantly longer survival than mice receiving vehicle (29 vs. 22 d, < 0.005) in a subcutaneous model. Convection-enhanced delivery demonstrated efficient retention of I-PARPi in orthotopic brain tumors, while quickly clearing from healthy brain tissue. Our results demonstrate I-PARPi's high potential as a therapeutic and highlight PARP's relevance as a target forradionuclide therapy. Radiation plays an integral role in brain tumor therapy, and radiolabeled PARP therapeutics could ultimately lead to improvements in the standard of care.

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“…This central role has been successfully leveraged for the development of various PARP inhibitors, both as a monotherapy and in combination with other therapeutics (17,18). Modified PARP inhibitors have also been widely used for tumor detection and imaging due to their cancer specificity and their high target-to-background contrast (14,15,(19)(20)(21)(22)(23)(24)(25); more recently, they have found theranostic applications (26).…”

Section: Introductionmentioning

confidence: 99%

Targeted Brain Tumor Radiotherapy Using an Auger Emitter

Pirovano

Jannetti

Carter

et al. 2020

Clinical Cancer Research

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Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades. Experimental design 123 I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger-and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair enzyme PARP1, specifically targets cancer cells, sparing healthy tissue, and carries a radioactive payload within reach of the cancer cells' DNA. Results The high relative biological efficacy of Auger electrons within their short range of action is leveraged to inflict DNA damage and cell death with high precision. The gamma ray emission of 123 I-MAPi allows for the imaging of tumor progression and therapy response, and for patient dosimetry calculation. Here we demonstrated the efficacy and specificity of this small molecule radiotheranostic in a complex preclinical model. In vitro and in vivo studies demonstrate high tumor uptake and a prolonged survival in mice treated with 123 I-MAPi when compared to vehicle controls. Different methods of drug delivery were investigated to develop this technology for clinical applications, including convection enhanced delivery (CED) and intrathecal injection. Conclusions Taken together, these results represent the first full characterization of an Augeremitting PARP inhibitor which demonstrate a survival benefit in mouse models of GBM and confirm the high potential of 123 I-MAPi for clinical translation.

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Iodinated benzimidazole PARP radiotracer for evaluating PARP1/2 expression in vitro and in vivo

Cited by 28 publications

References 39 publications

Molecular Imaging of PARP

Molecular Imaging of PARP

PARP-1–Targeted Radiotherapy in Mouse Models of Glioblastoma

Targeted Brain Tumor Radiotherapy Using an Auger Emitter

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