64 Cu-diacetyl-bis(N 4 -methylthiosemicarbazonate), 64 Cu-ATSM, continues to be investigated clinically as a PET agent both for delineation of tumor hypoxia and as an effective indicator of patient prognosis, but there are still aspects of the mechanism of action that are not fully understood. Methods: The retention of radioactivity in tumors after administration of 64 Cu-ATSM in vivo is substantially higher for tumors with a significant hypoxic fraction. This hypoxia-dependent retention is believed to involve the reduction of Cu-ATSM, followed by the loss of copper to cellular copper processing. To shed light on a possible role of copper metabolism in hypoxia targeting, we have compared 64 Cu retention in vitro and in vivo in CaNT and EMT6 cells or cancers after the administration of 64 Cu-ATSM or 64 Cu-acetate. Results: In vivo in mice bearing CaNT or EMT6 tumors, biodistributions and dynamic PET data are broadly similar for 64 Cu-ATSM and 64 Cu-acetate. Copper retention in tumors at 15 min is higher after injection of 64 Cu-acetate than 64 Cu-ATSM, but similar values result at 2 and 16 h for both. Colocalization with hypoxia as measured by EF5 immunohistochemistry is evident for both at 16 h after administration but not at 15 min or 2 h. Interestingly, at 2 h tumor retention for 64 Cuacetate and 64 Cu-ATSM, although not colocalizing with hypoxia, is reduced by similar amounts by increased tumor oxygenation due to inhalation of increased O 2 . In vitro, substantially less uptake is observed for 64 Cu-acetate, although this uptake had some hypoxia selectivity. Although 64 Cu-ATSM is stable in mouse serum alone, there is rapid disappearance of intact complex from the blood in vivo and comparable amounts of serum bound activity for both 64 Cu-ATSM and 64 Cu-acetate. Conclusion: That in vivo, in the EMT6 and CaNT tumors studied, the distribution of radiocopper from 64 Cu-ATSM in tumors essentially mirrors that of 64 Cu-acetate suggests that copper metabolism may also play a role in the mechanism of selectivity of Cu-ATSM.

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Background Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming.Methods A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy.Results S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p<0.001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r2=0.788; p<0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID).Conclusion We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.

Poly(ADP-ribose) polymerase (PARP) inhibitors are increasingly being studied as cancer drugs, as single agents, or as a part of combination therapies. Imaging of PARP using a radiolabeled inhibitor has been proposed for patient selection, outcome prediction, dose optimization, genotoxic therapy evaluation, and target engagement imaging of novel PARP-targeting agents. Methods: Here, via the copper-mediated 18 F-radiofluorination of aryl boronic esters, we accessed, for the first time (to our knowledge), the 18 F-radiolabeled isotopolog of the Food and Drug Administration–approved PARP inhibitor olaparib. The use of the 18 F-labeled equivalent of olaparib allows direct prediction of the distribution of olaparib, given its exact structural likeness to the native, nonradiolabeled drug. Results: 18 F-olaparib was taken up selectively in vitro in PARP-1–expressing cells. Irradiation increased PARP-1 expression and 18 F-olaparib uptake in a radiation-dose–dependent fashion. PET imaging in mice showed specific uptake of 18 F-olaparib in tumors expressing PARP-1 (3.2% ± 0.36% of the injected dose per gram of tissue in PSN-1 xenografts), correlating linearly with PARP-1 expression. Two hours after irradiation of the tumor (10 Gy), uptake of 18 F-olaparib increased by 70% ( P = 0.025). Conclusion: Taken together, we show that 18 F-olaparib has great potential for noninvasive tumor imaging and monitoring of radiation damage.