DOTA-tetrazine probes with modified linkers for tumor pretargeting.
- Läppchen T Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands; Department of Nuclear Medicine, Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetterstrasse 55, 79106 Freiburg, Germany; Department of Nuclear Medicine, Inselspital, Bern University Hospital and University of Bern, Freiburgstrasse, 3010 Bern, Switzerland.
- Rossin R Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands; Tagworks Pharmaceuticals BV, c/o Department of Nuclear Medicine and Radiology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands.
- van Mourik TR Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
- Gruntz G Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
- Hoeben FJM SyMO-Chem BV, Den Dolech 2, 5612 AZ, Eindhoven, The Netherlands.
- Versteegen RM SyMO-Chem BV, Den Dolech 2, 5612 AZ, Eindhoven, The Netherlands.
- Janssen HM SyMO-Chem BV, Den Dolech 2, 5612 AZ, Eindhoven, The Netherlands.
- Lub J Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
- Robillard MS Philips Research, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands; Tagworks Pharmaceuticals BV, c/o Department of Nuclear Medicine and Radiology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands. Electronic address: marc.robillard@tagworkspharma.com.
- 2017-10-14
Published in:
- Nuclear medicine and biology. - 2017
(177)Lu
Antibodies
Diels–Alder
Pretargeting
Tetrazine
Trans-cyclooctene
Animals
Biological Transport
Cell Line, Tumor
Heterocyclic Compounds, 1-Ring
Immunoconjugates
Isotope Labeling
Lutetium
Mice
Radiochemistry
Radioisotopes
Stereoisomerism
Tissue Distribution
English
INTRODUCTION
Pretargeted radioimmunoimaging and -therapy approaches building on the bioorthogonal inverse-electron-demand Diels-Alder (IEDDA) reaction between strained trans-cyclooctenes (TCO) and electron-deficient tetrazines (Tz) have yielded impressive results in recent years and have proven a vital alternative to biological pretargeting systems. After improvement of the TCO-antibody conjugates, we here report on our evaluation of a new series of radiolabeled Tz-probes.
METHODS
Four new Tz-probes were synthesized, radiolabeled with lutetium-177, and characterized in vitro in terms of lipophilicity, reactivity, and stability in PBS and mouse serum. The in vivo biodistribution profile and tumor-targeting potential of the probes were evaluated in LS174T tumor-bearing mice pretargeted with TCO-antibody conjugates using non-pretargeted mice as control.
RESULTS
Radiolabeling of all probes proceeded in high yields providing the 177Lu-labeled tetrazines in >95% radiochemical purity without any further purification. In mouse serum, half-lives of the probes varied between 8 and 13 h, with the exception of the most lipophilic probe, [177Lu]1b, with a serum half-life of less than 1 h. This probe also showed the fastest blood clearance (t1/2 = 5.4 min), more than 2-fold faster than PEG-linked probes [177Lu]3 and [177Lu]4, and even 3-fold faster than the other small probes without the PEG-linker, [177Lu]1a and [177Lu]2. In the pretargeting experiments, tumor uptake of the lead probe [177Lu]4 (~6 %ID/g) was most closely approached by [177Lu]2, followed by [177Lu]3 and [177Lu]1a. While all the smaller and more lipophilic probes suffered from increased liver uptake, the PEG-linked probe [177Lu]3 with its additional negative charge surprisingly showed the highest kidney uptake among all of the probes.
CONCLUSION
The in vitro performance of some of the new tetrazine probes turned out to be comparable to the established lead probe [177Lu]Lu-DOTA-PEG11-Tz ([177Lu]4). However, tumor pretargeting studies in vivo showed lower tumor uptake and increased uptake in non-target organs.
Pretargeted radioimmunoimaging and -therapy approaches building on the bioorthogonal inverse-electron-demand Diels-Alder (IEDDA) reaction between strained trans-cyclooctenes (TCO) and electron-deficient tetrazines (Tz) have yielded impressive results in recent years and have proven a vital alternative to biological pretargeting systems. After improvement of the TCO-antibody conjugates, we here report on our evaluation of a new series of radiolabeled Tz-probes.
METHODS
Four new Tz-probes were synthesized, radiolabeled with lutetium-177, and characterized in vitro in terms of lipophilicity, reactivity, and stability in PBS and mouse serum. The in vivo biodistribution profile and tumor-targeting potential of the probes were evaluated in LS174T tumor-bearing mice pretargeted with TCO-antibody conjugates using non-pretargeted mice as control.
RESULTS
Radiolabeling of all probes proceeded in high yields providing the 177Lu-labeled tetrazines in >95% radiochemical purity without any further purification. In mouse serum, half-lives of the probes varied between 8 and 13 h, with the exception of the most lipophilic probe, [177Lu]1b, with a serum half-life of less than 1 h. This probe also showed the fastest blood clearance (t1/2 = 5.4 min), more than 2-fold faster than PEG-linked probes [177Lu]3 and [177Lu]4, and even 3-fold faster than the other small probes without the PEG-linker, [177Lu]1a and [177Lu]2. In the pretargeting experiments, tumor uptake of the lead probe [177Lu]4 (~6 %ID/g) was most closely approached by [177Lu]2, followed by [177Lu]3 and [177Lu]1a. While all the smaller and more lipophilic probes suffered from increased liver uptake, the PEG-linked probe [177Lu]3 with its additional negative charge surprisingly showed the highest kidney uptake among all of the probes.
CONCLUSION
The in vitro performance of some of the new tetrazine probes turned out to be comparable to the established lead probe [177Lu]Lu-DOTA-PEG11-Tz ([177Lu]4). However, tumor pretargeting studies in vivo showed lower tumor uptake and increased uptake in non-target organs.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1016/j.nucmedbio.2017.09.001
- PMID 29028502
- Persistent URL
- https://sonar.ch/global/documents/45024
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