The Label Matters: μPET Imaging of the Biodistribution of Low Molar Mass <sup>89</sup>Zr and <sup>18</sup>F‑Labeled Poly(2-ethyl-2-oxazoline)

Poly­(2-alkyl-2-oxazoline)­s (PAOx) have received increasing interest for biomedical applications. Therefore, it is of fundamental importance to gain an in-depth understanding of the biodistribution profile of PAOx. We report the biodistribution of poly­(2-ethyl-2-oxazoline) (PEtOx) with a molar mass of 5 kDa radiolabeled with PET isotopes <sup>89</sup>Zr and <sup>18</sup>F. <sup>18</sup>F-labeled PEtOx is prepared by the strain-promoted azide–alkyne cycloaddition (SPAAC) of [<sup>18</sup>F]­fluoroethylazide to bicyclo[6.1.0]­non-4-yne (BCN)-functionalized PEtOx as many common labeling strategies were found to be unsuccessful for PEtOx. <sup>89</sup>Zr-labeled PEtOx is prepared using desferrioxamine end-groups as a chelator. Five kDa PEtOx shows a significantly faster blood clearance compared to PEtOx of higher molar mass while uptake in the liver is lower, indicating a minor contribution of the liver in excretion of the 5 kDa PEtOx. While [<sup>18</sup>F]-PEtOx displays a rapid and efficient clearance from the kidneys, 5 kDa [<sup>89</sup>Zr]-Df-PEtOx is not efficiently cleared over the time course of the study, which is most likely caused by trapping of <sup>89</sup>Zr-labeled metabolites in the renal tubules and not the polymer itself, demonstrating the importance of selecting the appropriate label for biodistribution studies.