[¹⁸F]FEPPA: Improved Automated Radiosynthesis, Binding Affinity, and Preliminary in Vitro Evaluation in Colorectal Cancer

The overexpression of the translocator protein (TSPO) has been amply reported for a variety of conditions, including neurodegenerative disorders, heart failure, and cancer. Thus, TSPO has been proposed as an excellent imaging biomarker, allowing, in this manner, to obtain an accurate diagnosis and to follow disease progression and therapy response. Accordingly, several radioligands have been developed to accomplish this purpose. In this work, we selected [¹⁸F]­FEPPA, as one of the clinical established tracers, and assessed its in vitro performance in colorectal cancer. Moreover, we setup an improved radiosynthesis method and assessed the in vitro binding affinity of the nonradioactive ligand toward the human TSPO. Our results show an excellent to moderate affinity, in the subnanomolar and nanomolar range, as well as the suitability of [¹⁸F]­FEPPA as an imaging agent for the TSPO in colorectal cancer

Additional file 1: of Assessing the kidney function parameters glomerular filtration rate and effective renal plasma flow with dynamic FDG-PET/MRI in healthy subjects

FDG TAC analysis. (DOCX 11 kb

sj-pdf-1-jcb-10.1177_0271678X231202336 - Supplemental material for [¹¹C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X231202336 for [11C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier by Severin Mairinger, Sarah Leterrier, Thomas Filip, Mathilde Löbsch, Jens Pahnke, Irene Hernández-Lozano, Johann Stanek, Nicolas Tournier, Markus Zeitlinger, Marcus Hacker, Oliver Langer and Thomas Wanek in Journal of Cerebral Blood Flow & Metabolism</p

Development and <i>In Vivo</i> 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

Development and <i>In Vivo</i> 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

Development of individual values of tumor glucose metabolism, assessed by PET as tumor-to-background ratio (TTB), in the therapy and in the control group between baseline and follow-up.

<p>Note the almost unidirectional decline of individual TTB values with a slight increase of TTB in only one tumor of the regorafenib-treated therapy group as well as a significantly (p<0.01) decreased mean TTB between day 0 and day 7. In the control group a uniform increase of individual TTB values can be observed with a significant (p<0.03) rise of mean TTB in the untreated colon carcinoma xenografts.</p

Representative line regression analysis for Spearman’s correlation coefficient between tumor plasma flow (ΔPF, mL/100mL/min) and tumor glucose metabolism (ΔTTB).

<p>Note the good and significant correlation between ΔPF and ΔTTB (r = 0.78, p<0.01) for the values of the therapy and the control group.</p

Representative axial TWIST MR images of a rat with a subcutaneous colon carcinoma xenograft over the left lateral flank after 7 days of regorafenib therapy.

<p>Note the hypointense tumor center corresponding to areas of beginning or present tumor necrosis and consecutively altered contrast media kinetics. For the assessment of tumor microcirculation a donut-shaped region-of-interest (red area) was drawn over vital tumor areas of the tumor periphery using semiquantitative AUC maps.</p

Development of individual values of tumor glucose metabolism, assessed by PET as tumor-to-background ratio (TTB), in the therapy and in the control group between baseline and follow-up.

<p>Note the almost unidirectional decline of individual TTB values with a slight increase of TTB in only one tumor of the regorafenib-treated therapy group as well as a significantly (p<0.01) decreased mean TTB between day 0 and day 7. In the control group a uniform increase of individual TTB values can be observed with a significant (p<0.03) rise of mean TTB in the untreated colon carcinoma xenografts.</p

Representative axial images of the investigated human colon carcinoma xenografts including tumor morphology (T2w images, top row), tumor perfusion parameter maps (middle row) and ¹⁸F-FDG-PET (bottom row) before therapy (left column) and after a one-week treatment course of regorafenib (right column). Note the significant decrease of tumor plasma flow (mL/100mL/min) and tumor glucose metabolism (TTB) after regorafenib therapy between baseline and follow-up.

<p>The hyperintense central tumor regions on the T2-weighted image after therapy are consistent with increasing, therapy-induced tumor necrosis.</p