TY  - JOUR
AU  - Krutzek, Fabian
AU  - Donat, Cornelius K
AU  - Ullrich, Martin
AU  - Zarschler, Kristof
AU  - Ludik, Marie-Charlotte
AU  - Feldmann, Anja
AU  - Loureiro, Liliana R
AU  - Kopka, Klaus
AU  - Stadlbauer, Sven
TI  - Design and Biological Evaluation of Small-Molecule PET-Tracers for Imaging of Programmed Death Ligand 1.
JO  - Cancers
VL  - 15
IS  - 9
SN  - 2072-6694
CY  - Basel
PB  - MDPI
M1  - DKFZ-2023-00977
SP  - 2638
PY  - 2023
AB  - Noninvasive molecular imaging of the PD-1/PD-L1 immune checkpoint is of high clinical relevance for patient stratification and therapy monitoring in cancer patients. Here we report nine small-molecule PD-L1 radiotracers with solubilizing sulfonic acids and a linker-chelator system, designed by molecular docking experiments and synthesized according to a new, convergent synthetic strategy. Binding affinities were determined both in cellular saturation and real-time binding assay (LigandTracer), revealing dissociation constants in the single digit nanomolar range. Incubation in human serum and liver microsomes proved in vitro stability of these compounds. Small animal PET/CT imaging, in mice bearing PD-L1 overexpressing and PD-L1 negative tumors, showed moderate to low uptake. All compounds were cleared primarily through the hepatobiliary excretion route and showed a long circulation time. The latter was attributed to strong blood albumin binding effects, discovered during our binding experiments. Taken together, these compounds are a promising starting point for further development of a new class of PD-L1 targeting radiotracers.
KW  - PD-L1 (Other)
KW  - PET imaging (Other)
KW  - immune checkpoint inhibitors (Other)
KW  - organic synthesis (Other)
KW  - radiotracer (Other)
KW  - small molecules (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37174103
C2  - pmc:PMC10177516
DO  - DOI:10.3390/cancers15092638
UR  - https://inrepo02.dkfz.de/record/276071
ER  -