• Journal of Radiopharmaceuticals and Molecular Probes
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• v.1 no.2
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• pp.123-129
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• 2015

$^{64}Cu$-labeled diacetyl-bis($N^4$-methylthiosemicarbazone) is a promising agent for internal radiation therapy and imaging of hypoxic tissues. In the study, we confirmed hypoxia regions in VX2 tumor implanted rabbits with injection $^{64}Cu$-ATSM and $^{18}F$-FDG using positron emission tomography (PET)/computed tomography (CT). PET images with $^{18}F$-FDG and $^{64}Cu$-ATSM were obtained for 40 min by dynamic scan and additional delayed PET images of $^{64}Cu$-ATSM the acquired up to 48 hours. Correlation between intratumoral $O_2$ level and $^{64}Cu$-ATSM PET image was analyzed. $^{64}Cu$-ATSM and $^{18}F$-FDG were intravenously co-injected and the tumor was dissected and cut into slices for a dual-tracer autoradiographic analysis. In the PET imaging, $^{64}Cu$-ATSM in VX2 tumors displayed a specific uptake in hypoxic region for48 h. The uptake pattern of $^{64}Cu$-ATSM in VX2 tumor at 24 and 48 h did not match to the $^{18}F$-FDG. Through ROI analysis, in the early phase (dynamic scan), $^{18}F$-FDG has positive correlation with $^{64}Cu$-ATSM but late phase (24 and 48 h) of the $^{64}Cu$-ATSM showed negative correlation with $^{18}F$-FDG. High uptake of $^{64}Cu$-ATSM in hypoxic region was responded with significant decrease of oxygen pressure, which confirmed by $^{64}Cu$-ATSM PET imaging and autoradiographic analysis. In conclusion, $^{64}Cu$-ATSM can utilize for specific targeting of hypoxic region in tumor, and discrimination between necrotic- and viable hypoxic tissue.

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.9 no.2
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• pp.101-105
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• 2023

Cu(II) diacetyl-di(N⁴-methylthiosemicarbazone), also known as Cu(II)-ATSM, is a popular copper-complexed thiosemicarbazone derivative that has been widely studied for hypoxia. [⁶⁴Cu]Cu-ATSM has emerged as an effective tracer for positron emission tomography imaging to functionally characterize hypoxic tumors. However, understanding the precise mechanism of cellular uptake and metabolism of Cu(II)-ATSM remains a controversial task in which different hypotheses have been proposed. Herein, we will elucidate the current findings regarding the hypoxic uptake mechanism of Cu(II)-ATSM. Particularly, we will investigate the cell internalization mechanism and intracellular reduction of Cu(II)-ATSM.

• Journal of Radiopharmaceuticals and Molecular Probes
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• v.9 no.2
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• pp.81-85
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• 2023

Hydrogen sulfide (H₂S), recognized as the third gasotransmitter with specific implications for inflammation and hypoxia, exhibits affinity for ⁶⁴Cu immobilization. This study explores the viability of ⁶⁴Cu-labeled PET tracers in detecting endogenous H₂S. In vitro reactivity experiments involved evaluating the interaction between various concentrations of NaHS and ⁶⁴Cu-labeled chelators at 37℃ in a shaking incubator. In vivo molecular PET imaging studies were conducted using two distinct mouse models. An acute inflammation model, induced with carrageenan, involved administering 2.22 MBq/100 µL of [⁶⁴Cu]Cu-ATSM or [⁶⁴Cu]Cu-Cyclen intravenously 4 hours post-inflammation induction, with subsequent PET imaging in static 5 min mode. For the NaHS implantation model, NaHS dissolved in Matrigel was subcutaneously injected into the right dorsal region of BALB/c mice, followed by intravenous injection of radiotracers (2.22 MBq/100 µL) 1 hour later, and subsequent PET imaging. The optimized labeling condition involved dissolving 10 ㎍ of chelators in ammonium acetate buffer and reacting at 60℃ for 20 minutes. Both [⁶⁴Cu]Cu-Cyclen and [⁶⁴Cu]Cu-ATSM reacted with various concentrations of NaHS to form insoluble ⁶⁴CuS. High uptake of [⁶⁴Cu]Cu-ATSM and [⁶⁴Cu]Cu-Cyclen in acute inflammatory lesions in the mouse right footpad and the NaHS implantation model suggests their potential as imaging agents for inflammation and H₂S in vivo. In conclusion, optimized [⁶⁴Cu]Cu-ATSM and [⁶⁴Cu]Cu-Cyclen labeling conditions for endogenous H₂S imaging were established, confirming insoluble ⁶⁴CuS both in vitro and in vivo. [⁶⁴Cu]Cu-ATSM and [⁶⁴Cu]Cu-Cyclen hold promise as diagnostic agents targeting endogenous H₂S in various diseases associated with inflammation and hypoxia.