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123I-MAPi, a novel PARP1-targeted Auger radiotherapeutic has shown promising results in pre-clinical glioma model. Currently, 123I-MAPi is synthesized using multistep synthesis that results in modest yields and low molar activities (MA) that limits the ability to translate this technology for human studies where high doses are administered. Therefore, new methods are needed to synthesize 123I-MAPi in high activity yields (AY) and improved MA to facilitate clinical translation and multicenter trials. 123I-MAPi was prepared in a single step via 123I-iododetannylation of the corresponding tributylstannane precursor. In vitro internalization assay, subcellular fractionation and confocal microscopy where used to evaluate the performance of 123I-MAPi in a small cell lung cancer model. 123I-MAPi was synthesized in a single step from the corresponding stannane precursor in AY of 45 ± 2% and MA of 11.8 ± 4.8 GBq µmol−1. In vitro in LX22 cells showed rapid internalization (5 min) with accumulation found predominantly in the membrane, nucleus and chromatin of the cell as determined by subcellular fractionation. Here, we have developed an improved radiosynthesis of 123I-MAPi, an Auger theranostic agent. This process was achieved using a single step, 123I-iododestannylation reaction from the corresponding stannane precursor in good AY and MA. 123I-MAPi was evaluated in vitro in a small cell lung cancer model with high PARP expression, rapid internalization and high nuclear uptake shown. [ABSTRACT FROM AUTHOR]

Background. Human papillomavirus- (HPV-) associated oropharyngeal squamous cell carcinomas (OPSCCs) are clinically and pathologically distinct from HPV-negative tumors. Here, we explore whether HPV affects functional biomarkers, including γ H2AX, RAD51, and PARP1. Moreover, the role of [18F]PARPi as a broadly applicable imaging tool for head and neck carcinomas is investigated. Methods. HPV-positive and HPV-negative cell lines were used to evaluate the γ H2AX, RAD51, and PARP1 expression with immunoblotting and immunofluorescence. Effects of external beam ionizing radiation were investigated in vitro, and survival was investigated via colony-formation assay. [18F]PARPi uptake experiments were performed on HPV-negative and HPV-positive cell lines to quantify PARP1 expression. PARP1 IHC and γ H2AX foci were quantified using patient-derived oropharyngeal tumor specimens. Results. Differences in DNA repair were detected, showing higher RAD51 and γ H2AX expression in HPV-positive cell lines. Clonogenic assays confirm HPV-positive cell lines to be significantly more radiosensitive. PARP1 expression levels were similar, irrespective of HPV status. Consequently, [18F]PARPi uptake assays demonstrated that this tracer is internalized in cell lines independently from their HPV status. Conclusion. The HPV status, often used clinically to stratify patients, did not affect PARP1 levels, suggesting that PARP imaging can be performed in both HPV-positive and HPV-negative patients. This study confirms that the PET imaging agent [18F]PARPi could serve as a general clinical tool for oropharyngeal cancer patients. [ABSTRACT FROM AUTHOR]

Background. Human papillomavirus- (HPV-) associated oropharyngeal squamous cell carcinomas (OPSCCs) are clinically and pathologically distinct from HPV-negative tumors. Here, we explore whether HPV affects functional biomarkers, including γ H2AX, RAD51, and PARP1. Moreover, the role of [18F]PARPi as a broadly applicable imaging tool for head and neck carcinomas is investigated. Methods. HPV-positive and HPV-negative cell lines were used to evaluate the γ H2AX, RAD51, and PARP1 expression with immunoblotting and immunofluorescence. Effects of external beam ionizing radiation were investigated in vitro, and survival was investigated via colony-formation assay. [18F]PARPi uptake experiments were performed on HPV-negative and HPV-positive cell lines to quantify PARP1 expression. PARP1 IHC and γ H2AX foci were quantified using patient-derived oropharyngeal tumor specimens. Results. Differences in DNA repair were detected, showing higher RAD51 and γ H2AX expression in HPV-positive cell lines. Clonogenic assays confirm HPV-positive cell lines to be significantly more radiosensitive. PARP1 expression levels were similar, irrespective of HPV status. Consequently, [18F]PARPi uptake assays demonstrated that this tracer is internalized in cell lines independently from their HPV status. Conclusion. The HPV status, often used clinically to stratify patients, did not affect PARP1 levels, suggesting that PARP imaging can be performed in both HPV-positive and HPV-negative patients. This study confirms that the PET imaging agent [18F]PARPi could serve as a general clinical tool for oropharyngeal cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: Lymphokine-activated killer T cell-originated protein kinase (TOPK) is a fairly new cancer biomarker with great potential for clinical applications. The labeling of a TOPK inhibitor with F-18 can be exploited for positron emission tomography (PET) imaging allowing more accurate patient identification, stratification, and disease monitoring.Procedures: [18F]FE-OTS964 was produced starting from OTS964, a preclinical drug which specifically binds to TOPK, and using a two-step procedure with [18F]fluoroethyl p-toluenesulfonate as a prosthetic group. Tumors were generated in NSG mice by subcutaneous injection of U87 glioblastoma cells. Animals were injected with [18F]FE-OTS964 and PET imaging and ex vivo biodistribution analysis was carried out.Results: [18F]FE-OTS964 was successfully synthesized and validated in vivo as a PET imaging agent. The labeling reaction led to 15.1 ± 7.5 % radiochemical yield, 99 % radiochemical purity, and high specific activity. Chemical identity of the radiotracer was confirmed by co-elution on an analytical HPLC with a cold-labeled standard. In vivo PET imaging and biodistribution analysis showed tumor uptake of 3.06 ± 0.30 %ID/cc, which was reduced in animals co-injected with excess blocking dose of OTS541 to 1.40 ± 0.42 %ID/cc.Conclusions: [18F]FE-OTS964 is the first TOPK inhibitor for imaging purposes and may prove useful in the continued investigation of the pharmacology of TOPK inhibitors and the biology of TOPK in cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: 123 I-MAPi, a novel PARP1-targeted Auger radiotherapeutic has shown promising results in pre-clinical glioma model. Currently, 123 I-MAPi is synthesized using multistep synthesis that results in modest yields and low molar activities (MA) that limits the ability to translate this technology for human studies where high doses are administered. Therefore, new methods are needed to synthesize 123 I-MAPi in high activity yields (AY) and improved MA to facilitate clinical translation and multicenter trials., Materials and Methods: 123 I-MAPi was prepared in a single step via 123 I-iododetannylation of the corresponding tributylstannane precursor. In vitro internalization assay, subcellular fractionation and confocal microscopy where used to evaluate the performance of 123 I-MAPi in a small cell lung cancer model., Results: 123 I-MAPi was synthesized in a single step from the corresponding stannane precursor in AY of 45 ± 2% and MA of 11.8 ± 4.8 GBq µ mol -1 . In vitro in LX22 cells showed rapid internalization (5 min) with accumulation found predominantly in the membrane, nucleus and chromatin of the cell as determined by subcellular fractionation., Conclusions: Here, we have developed an improved radiosynthesis of 123 I-MAPi, an Auger theranostic agent. This process was achieved using a single step, 123 I-iododestannylation reaction from the corresponding stannane precursor in good AY and MA. 123 I-MAPi was evaluated in vitro in a small cell lung cancer model with high PARP expression, rapid internalization and high nuclear uptake shown.

Despite efforts in prevention, cervical cancer still presents with a high worldwide incidence and remains a great problem in public health, especially in low-income countries. Screening programs, such as colposcopy with Papanicolaou testing, have greatly improved mortality rates. However, the agents currently used to delineate those lesions (topical application of acetic acid or Lugol iodine) lack specificity and sometimes can lead to unnecessary biopsies or even cervical excisions. A tool to enable in vivo histology to quickly and quantitatively distinguish between tumor, dysplastic tissue, and healthy tissue would be of great clinical interest. Methods: Here, we describe the use of PARPi-FL, a fluorescent inhibitor of poly[adenosine diphosphate-ribose]polymerase 1 (PARP1), which is a nuclear enzyme that is overexpressed in cancer when compared with the normal surrounding tissues. We exploit its use as an optical imaging agent to specifically target PARP1 expression, which was demonstrated to be higher in cervical cancer than the normal surrounding tissue. Results: After topical application of PARPi-FL on freshly excised cone biopsy samples, the nuclei of tumor cells emitted a specific fluorescent signal that could be visualized using a handheld fluorescence confocal microscope. Conclusion: This approach has the potential to improve in vivo identification of tumor cells during colposcopy examination, allowing a rapid, noninvasive, and accurate histopathologic assessment., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [ 18 F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes., Methods: We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [ 18 F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [ 18 F]PARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner. Lesion diagnosis was established by pathology when available or by Response Assessment in Neuro-Oncology (RANO) or RANO-BM response criteria. Resected tissue also underwent PARPi-FL staining and PARP1 immunohistochemistry., Results: In a preclinical mouse model, we illustrated that [ 18 F]PARPi crossed the blood-brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high [ 18 F]PARPi uptake on PET/MR in active brain cancers and low uptake in treatment-related changes independent of blood-brain barrier disruption. Immunohistochemistry results confirmed higher PARP1 expression in cancerous than in noncancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with an excess unlabeled PARP inhibitor in patient cancer biospecimen., Conclusions: Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [ 18 F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

The immune function within the tumor microenvironment has become a prominent therapeutic target, with tumor-associated macrophages (TAMs) playing a critical role in immune suppression. We propose an 89 Zr-labeled high-density lipoprotein ( 89 Zr-HDL) nanotracer as a means of monitoring response to immunotherapy. Methods: Female MMTV-PyMT mice were treated with pexidartinib, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, to reduce TAM density. The accumulation of 89 Zr-HDL within the tumor was assessed using PET/CT imaging and autoradiography, whereas TAM burden was determined using immunofluorescence. Results: A significant reduction in 89 Zr-HDL accumulation was observed in PET/CT images, with 2.9% ± 0.3% and 3.7% ± 0.2% injected dose/g for the pexidartinib- and vehicle-treated mice, respectively. This reduction was corroborated ex vivo and correlated with decreased TAM density. Conclusion: These results support the potential use of 89 Zr-HDL nanoparticles as a PET tracer to quickly monitor the response to CSF1R inhibitors and other therapeutic strategies targeting TAMs., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Twenty million Americans suffer from peripheral nerve injury caused by trauma and medical disorders, resulting in a broad spectrum of potentially debilitating side effects. In one out of four cases, patients identify surgery as the root cause of their nerve injury. Particularly during tumor resections or after traumatic injuries, tissue distortion and poor visibility can challenge a surgeon's ability to precisely locate and preserve peripheral nerves. Intuitively, surgical outcomes would improve tremendously if nerves could be highlighted using an exogeneous contrast agent. In clinical practice, however, the current standard of care-visual examination and palpation-remains unchanged. To address this unmet clinical need, we explored the expression of voltage-gated sodium channel Na v 1.7 as an intraoperative marker for the peripheral nervous system. We show that expression of Na v 1.7 is high in peripheral nerves harvested from both human and mouse tissue. We further show that modification of a Na v 1.7-selective peptide, Hsp1a, can serve as a targeted vector for delivering a fluorescent sensor to the peripheral nervous system. Ex vivo, we observe a high signal-to-noise ratio for fluorescently labeled Hsp1a in both histologically prepared and fresh tissue. Using a surgical fluorescent microscope, we show in a simulated clinical scenario that the identification of mouse sciatic nerves is possible, suggesting that fluorescently labeled Hsp1a tracers could be used to discriminate nerves from their surrounding tissues in a routine clinical setting.