Chelator-based non-peptidic radiotracers for PET imaging of PD-L1 with copper-64


Chelator-based non-peptidic radiotracers for PET imaging of PD-L1 with copper-64

Krutzek, F.; Donat, C.; Ullrich, M.; Loureiro, L. R.; Kopka, K.; Stadlbauer, S.

Objective: The programmed cell death-ligand 1 (PD-L1) is upregulated on many different cancers and allows the tumor cells to evade immune response through binding to the PD-1 receptor.[1] Monoclonal antibodies, i.e. checkpoint inhibitors, are able to break this blockade and thus reactivate the immune system.[2] However, only 30% of the patients respond to antibody-based immunotherapy. Because PD-L1 is heterogeneously expressed within and across tumor sites, there is an urgent clinical need for a non-invasive, diagnostic imaging approach helping for therapy decision. Radiotracers for PET and SPECT imaging are able to meet these requirements. Especially small molecules are favourable, because of their short clearance times and for providing high imaging contrast.[3]

Methods: Modification of two literature known small molecule PD-L1 inhibitors with water-solubilizing groups, different linkers and a DOTA chelator resulted in six different radioligands. Labeling was performed with Cu-64 (HZDR, 30 MeV TR-FLEX cyclotron) and binding affinities to PD-L1 were determined in vitro on transduced PC3 cells stably overexpressing human PD-L1. Qualitative PET scans (nanoSCAN PET/CT scanner, Mediso) were performed in NMRI-FoxN1-nude mice bearing PC3-hPD-L1 xenografted tumors.

Results: Organic synthesis started from biaryl building blocks (R1 = H, R2 = Br and R1 = R2 = Me), which underwent a Mitsunobu reaction with the central chloroaryl moiety. The bis(sulfonic acid) group was attached via a sarcosine spacer. Three different linker structures were synthesized and attached by Cu(I)-catalyzed click reaction. Synthesis was finished with DOTA conjugation and subsequent quantitative labeling with Cu-64 under standard labeling conditions was achieved. Using the shake flask method, log(D) values ranging from –1.5 to –2.5 were obtained. Saturation binding assays revealed that biphenyl compounds with R1 = R2 = Me showed promising binding affinities to PD-L1 (KD between 60 and 123 nM). In micro-PET experiments, the radioligands exhibited unusual high circulation times. PET images obtained after 15 h p.i. showed the highest tumor uptake and moderate uptake in the liver.
Conclusion: A library of new PD-L1 targeting non-peptide radiotracers based on small molecule lead structures bearing water-soluble groups and a chelator was successfully synthesized. All compounds showed moderate binding affinities toward PD-L1. Qualitative PET/CT scans showed a moderate uptake in PD-L1 positive tumors. For improved pharmacokinetics the lipophilicity should be further reduced and DOTA replaced by more optimal chelators such as NODAGA to avoid possible copper transchelation in the liver.

References:

[1] M. A. Postow, M. K. Callahan, J. D. Wolchok, J Clin Oncol 2015, 33, 1974-1982.
[2] S. L. Topalian, C. G. Drake, D. M. Pardoll, Cancer cell 2015, 27, 450-461.
[3] S. Chatterjee, W. G. Lesniak, S. Nimmagadda, Mol. Imaging 2017, 16, 1-5.

  • Lecture (Conference)
    International Symposium on Radiopharmaceutical Sciences, 29.05.-02.06.2022, Nantes, France

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Publ.-Id: 35962