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[F]-5-fluorocytosine-arabinoside ( 2) and [F]-5-fluorocyclocytidine ( 4) were prepared by reaction of [F]-acetylhypofluorite with cytosine-arabinoside ( 1) or cyclocytidine ( 3) in acetic acid and were isolated in an overall radiochemical yield of 20% and 9%, respectively. The biodistribution of both radiopharmaceuticals was determined in melanoma bearing Syrian golden hamsters. It was found that 2 is a good tumour-localizing agent for pigmented and non-pigmented Greene melanoma. [ABSTRACT FROM AUTHOR]

Linker instability and impaired tumor targeting can affect the tolerability and efficacy of antibody-drug conjugates (ADCs). To improve these ADC characteristics, we recently described the use of a metal-organic linker, [ethylenediamineplatinum(II)] 2+ , herein called Lx Initial therapy studies in xenograft-bearing mice revealed that trastuzumab- Lx -auristatin F (AF) outperformed its maleimide benchmark trastuzumab-mal-AF and the Food and Drug Administration-approved ado-trastuzumab emtansine, both containing conventional linkers. In this study, we aimed to characterize Lx -based ADCs for in vivo stability and tumor targeting using 195m Pt and 89 Zr. Methods: The γ-emitter 195m Pt was used to produce the radiolabeled Lx [ 195m Pt] Lx 89 Zr-Desferrioxamine ( 89 Zr-DFO) was conjugated to trastuzumab either via [ 195m Pt] Lx (to histidine residues) or conventionally (to lysine residues) in order to monitor the biodistribution of antibody, payload, and linker separately. Linker stability was determined by evaluating the following ADCs for biodistribution in NCI-N87 xenograft-bearing nude mice 72 h after injection: trastuzumab-[ 195m Pt] Lx -DFO- 89 Zr, trastuzumab-[ 195m Pt] Lx -AF, and 89 Zr-DFO-(Lys)trastuzumab (control), all having drug-to-antibody ratios (DARs) of 2.2-2.5. To assess the influence of DAR on biodistribution, 89 Zr-DFO-(Lys)trastuzumab- Lx -AF with an AF-to-antibody ratio of 0, 2.6, or 5.2 was evaluated 96 h after injection. Results: Similar biodistributions were observed for trastuzumab-[ 195m Pt] Lx -DFO- 89 Zr, trastuzumab-[ 195m Pt] Lx -AF, and 89 Zr-DFO-(Lys)trastuzumab irrespective of the isotope used for biodistribution assessment. The fact that Lx follows the antibody biodistribution indicates that the payload- Lx bond is stable in vivo. Uptake of the 3 conjugates, as percentage injected dose (%ID) per gram of tissue, was about 30 %ID/g in tumor tissue but less than 10 %ID/g in most healthy tissues. Trastuzumab-[ 195m Pt] Lx -AF (DAR 2.2) showed a tendency toward faster blood clearance and an elevated liver uptake, which increased significantly to 28.1 ± 4.2 %ID/g at a higher DAR of 5.2, as revealed from the biodistribution and PET imaging studies. Conclusion: As shown by 195m Pt/ 89 Zr labeling, ADCs containing the Lx linker are stable in vivo. In the case of trastuzumab- Lx -AF (DARs 2.2 and 2.6), an unimpaired biodistribution was demonstrated., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)