Development and In Vivo Evaluation of Small-Molecule Ligands for Positron Emission Tomography of Immune Checkpoint Modulation Targeting Programmed Cell Death 1 Ligand 1.

A substantial portion of patients do not benefit from programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) checkpoint inhibition therapies, necessitating a deeper understanding of predictive biomarkers. Immunohistochemistry (IHC) has played a pivotal role in assessing PD-L1 expression, but small-molecule positron emission tomography (PET) tracers could offer a promising avenue to address IHC-associated limitations, i.e., invasiveness and PD-L1 expression heterogeneity. PET tracers would allow for improved quantification of PD-L1 through noninvasive whole-body imaging, thereby enhancing patient stratification. Here, a large series of PD-L1 targeting small molecules were synthesized, leveraging advantageous substructures to achieve exceptionally low nanomolar affinities. Compound 5c emerged as a promising candidate (IC50 = 10.2 nM) and underwent successful carbon-11 radiolabeling. However, a lack of in vivo tracer uptake in xenografts and notable accumulation in excretory organs was observed, underscoring the challenges encountered in small-molecule PD-L1 PET tracer development. The findings, including structure-activity relationships and in vivo biodistribution data, stand to illuminate the path forward for refining small-molecule PD-L1 PET tracers.

Additively manufactured test phantoms for mimicking soft tissue radiation attenuation in CBCT using Polyjet technology.

OBJECTIVES: To develop and validate a simple approach for building cost-effective imaging phantoms for Cone Beam Computed Tomography (CBCT) using a modified Polyjet additive manufacturing technology where a single material can mimic a range of human soft-tissue radiation attenuation. MATERIALS AND METHODS: Single material test phantoms using a cubic lattice were designed in 3-Matic 15.0 software . Keeping the individual cubic lattice volume constant, eight different percentage ratio (R) of air: material from 0% to 70% with a 10% increment were assigned to each sample. The phantoms were printed in three materials, namely Vero PureWhite, VeroClear and TangoPlus using Polyjet technology. The CT value analysis, non-contact profile measurement and microCT-based volumetric analysis was performed for all the samples. RESULTS: The printed test phantoms produced a grey value spectrum equivalent to the radiation attenuation of human soft tissues in the range of -757 to +286 HU on CT. The results from dimensional comparison analysis of the printed phantoms with the digital test phantoms using non-contact profile measurement showed a mean accuracy of 99.07 % and that of micro-CT volumetric analysis showed mean volumetric accuracy of 84.80-94.91%. The material and printing costs of developing 24 test phantoms was 83.00 Euro. CONCLUSIONS: The study shows that additive manufacturing-guided macrostructure manipulation modifies successfully the radiographic visibility of a material in CBCT imaging with 1 mm3 resolution, helping customization of imaging phantoms.