Perfusion and the vascular architecture. In our study, we found that
Perfusion and the vascular architecture. In our study, we found that the clearance from muscle tissue was unaffected by the different breathing protocols, whereas the tumor clearance showed a tendency toward higher clearances with longer oxygen incubation times (Figure 6). This contrasts with the findings from Reischl et al. who reported that the reduced T/M ratio under carbogen (95 oxygen, 5 CO2) breathing was related to a reduced muscle washout whereas the tumor clearance remained unchanged [17]. On the other hand, Mortensen et al. observed in mammary carcinoma bearing carbogen breathing mice primarily lower [ 18 F]FAZA tumor to blood ratios compared to air breathing mice [36]. Furthermore, the muscle tissue was not affected by the different breathing protocols, as was the case for the tumor tissue; this also illustrate the specificity of [18F] FAZA for hypoxic tumor tissue. A potential benefit of nitroimidazoles such as [18F]FAZA might be the underlying bioreductive mechanism in hypoxic cells. [ 18 F] FAZA is mainly reduced by cytosolic xanthine oxidase upon entering the hypoxic cell and is only reduced to a small extent by the mitochondrial respiratory chain complex I [20]. Thus, it follows that the reduction of [18F]FAZA is not dependent upon NADH levels (or the “redox-state” of the cell) but is directly linked to the intracellular oxygen level. This is also true for other nitroimidazoles. To our knowledge, this is the first study to correlate [18F]FAZA tumor uptake with different oxygen breathing protocols (P0, P1, P2) to determine the cell oxygen level-dependent uptake of [18F]FAZA as other investigators (Piert et al. and Reischl et al.) analyzed exclusively littermates that AZD4547 price breathed air or 95 oxygen with 5 CO2 [14]. The tumor-to-muscle ratios of [18F]FAZA at 2 h and 3 h p.i. were higher using the P0 breathing protocol (21 oxygen) compared to the P1 and P2 oxygen breathing protocols. [18F]FAZA tumor uptake showed an inverse correlation with oxygen supply, which confirms the specificity for hypoxia detection (Figure 6). Surprisingly, the P0 breathing protocol and the P1 andP2 oxygen breathing protocols did not show significant differences in the T/M ratios 1 h post [ 18 F]FAZAinjection. Subsequently, the similar tracer uptake in tumors in the P1 and P2 breathing protocols during the investigations 2-3 h p.i. clearly indicate that the crucial uptake phase for [18F]FAZA occurs during the first hour after injection because air breathing in between the 1 h, 2 h and 3 h PET scans (P2) did not significantly impair [18F] FAZA uptake compared to the oxygen breathing protocol (P1). Sequential [ 18 F]FDG (Figure 5A) and [ 18 F] FAZA (Figure 5C) scans followed by ex vivo H E (Figure 5B) and pimonidazole immunostaining (Figure 5D and 5E) strongly support the feasibility of [18F]FAZA in terms of tumor hypoxia imaging.Conclusion We could not detect any difference in [18F]FAZA uptake regarding the two tumor types and the tumor size. The uptake and clearance of [18F]FAZA in carcinomas was dependent on the oxygen supply, especially during the time prior to and until 1 h after [18 F]FAZA-injection, whereas the uptake and clearance of [18F]FAZA in muscle tissue was not affected by different oxygen breathing protocols. The different oxygen breathing protocols clearly indicate that [ 18 F]FAZA is a valid marker for hypoxia because higher tracer uptake in tumors correlates with PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26104484 decreased oxygen supply. The critical time for [18F]FAZA uptake is th.