Abstract
The benefits of PET imaging of tumor hypoxia in patient management has been demonstrated in many examples and with various tracers over the last years. Although, the optimal hypoxia imaging agent has yet to be found, 2-nitroimidazole (azomycin) sugar derivatives—mimicking nucleosides—have proven their potential with [18F]FAZA ([18F]fluoro-azomycin-α-arabinoside) as a prominent representative in clinical use. Still, for all of these tracers, cellular uptake by passive diffusion is postulated with the disadvantage of slow kinetics and low tumor-to-background ratios. We recently evaluated [18F]fluoro-azomycin-β-deoxyriboside (β-[18F]FAZDR), with a structure more similar to nucleosides than [18F]FAZA and possible interaction with nucleoside transporters. For a deeper insight, we comparatively studied the interaction of FAZA, β-FAZA, α-FAZDR and β-FAZDR with nucleoside transporters (SLC29A1/2 and SLC28A1/2/3) in vitro, showing variable interactions of the compounds. The highest interactions being for β-FAZDR (IC50 124 ± 33 µM for SLC28A3), but also for FAZA with the non-nucleosidic α-configuration, the interactions were remarkable (290 ± 44 µM {SLC28A1}; 640 ± 10 µM {SLC28A2}). An improved synthesis was developed for β-FAZA. For a PET study in tumor-bearing mice, α-[18F]FAZDR was synthesized (radiochemical yield: 15.9 ± 9.0% (n = 3), max. 10.3 GBq, molar activity > 50 GBq/µmol) and compared to β-[18F]FAZDR and [18F]FMISO, the hypoxia imaging gold standard. We observed highest tumor-to-muscle ratios (TMR) for β-[18F]FAZDR already at 1 h p.i. (2.52 ± 0.94, n = 4) in comparison to [18F]FMISO (1.37 ± 0.11, n = 5) and α-[18F]FAZDR (1.93 ± 0.39, n = 4), with possible mediation by the involvement of nucleoside transporters. After 3 h p.i., TMR were not significantly different for all 3 tracers (2.5–3.0). Highest clearance from tumor tissue was observed for β-[18F]FAZDR (56.6 ± 6.8%, 2 h p.i.), followed by α-[18F]FAZDR (34.2 ± 7.5%) and [18F]FMISO (11.8 ± 6.5%). In conclusion, both isomers of [18F]FAZDR showed their potential as PET hypoxia tracers. Differences in uptake behavior may be attributed to a potential variable involvement of transport mechanisms.
Highlights
Nowadays, the value of tumor hypoxia imaging for patient stratification, targeted and individualized therapy, and the monitoring thereof is undeniable [1,2,3,4,5,6]
We investigated α-[18F]FAZDR (Figure 2A), where we expected hypoxia targeting in tumor tissue, but no major involvement of nucleoside transporters regarding tissue uptake. α-[18F]FAZDR-to-muscle ratios (TMR) at 1 h p.i. were higher compared to TMR of [18F]FMISO at 1 h p.i. (α-[18F]FAZDR: 1.93 ± 0.39, n = 4; [18F]FMISO: 1.37 ± 0.11, n = 5; Figure 2B)
One could conclude from this body of data that hypoxia tracer image contrast consists of three different components, which are theoretically influenced by the contribution of nucleoside transporters: (i) Free tracer in tissue or in the fractional blood volume of target and reference tissue, (ii) non- bound in target and reference tissue, and (iii) bound or trapped in target tissue
Summary
The value of tumor hypoxia imaging for patient stratification, targeted and individualized therapy, and the monitoring thereof is undeniable [1,2,3,4,5,6]. [18F]FAZA has not been identified in detail, yet it is assumed to be via passive diffusion, as an alpha-configurated nucleoside derivative should not be transported actively It has been conceptualized in the past [13,14,15,16] that uptake and retention of 2-nitroimidazole-sugars in hypoxic tumor tissue can be altered by permutation of both, sugar moiety and stereochemistry at the anomeric carbon atom (2-nitroimidazole linked)—with the rationale to take advantage of transport mechanisms involving nucleoside transporters. The mouse colon carcinoma model could be chosen, as mouse transporters exhibit close similarity to human nucleoside transporters [22] With this comparative study, we sought to gain further insight into the importance and influence of the sugar moiety and configuration of 2-nitroimidazole at the anomeric carbon atom on tracer uptake and image contrast. Scheme 1.1T. hTreher-esete-sptespyntshyenstihseosfistheo5f -flthueoro5 ́n-fulucloeroosidneuacnleaolosgidβe-FAanZaAlo,gstaβr-tFinAgZfrAo,ms1t-a(r2ti-nOg-acfreotymlβ1-(D2- ́a-Ora-baicneotyful-raβn-Dos-yalr)a-2b-iniotfruorimanidosayzlo)l-e2-(nβi-t1r;o[i2m5i]d).aRzoealege(nβt-s1;fo[r2a5n])d. yRieealdgsenotfsthfoerinadnivdidyuiealldssteopfs athre ginivdeivnidinutahlestsecphsemare.given in the scheme
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
