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3. Multi-parameter optimization: Development of a morpholin-3-one derivative with an improved kinetic profile for imaging monoacylglycerol lipase in the brain

Author

He, Yingfang, Grether, Uwe, Taddio, Marco F., Meier, Carla, Keller, Claudia, Edelmann, Martin R., Honer, Michael, Huber, Sylwia, Wittwer, Matthias B., Heer, Dominik, Richter, Hans, Collin, Ludovic, Hug, Melanie N., Hilbert, Manuel, Postmus, Annemarieke G.J., Stevens, Anna Floor, van der Stelt, Mario, Krämer, Stefanie D., Schibli, Roger, Mu, Linjing, and Gobbi, Luca C.

Published
2022
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4. Preclinical evaluation of 225Ac-labeled minigastrin analog DOTA-CCK-66 for Targeted Alpha Therapy.

Author

Holzleitner, Nadine, Vilangattil, Meryl, Swaidan, Abir, Garcia-Prada, Clara Diaz, Taddio, Marco F., Jeanjean, Pauline, Mona, Christine E., Lapa, Constantin, Casini, Angela, Günther, Thomas, and Carlucci, Giuseppe

Subjects
POSITRON emission tomography, MEDICAL sciences, MEDULLARY thyroid carcinoma, ANIMAL welfare, COMPUTED tomography
Abstract

The recently developed metabolically more stable minigastrin derivative, DOTA-CCK-66, displayed promising preclinical data when labeled either with 68Ga or 177Lu. First positron emission tomography/computed tomography (PET/CT) imaging using [68Ga]Ga-DOTA-CCK-66 in two patients suffering from medullary thyroid carcinoma (MTC) displayed a favorable biodistribution profile. Here, we aim to investigate the therapeutic potential of [225Ac]Ac-DOTA-CCK-66 as a targeted α-therapy (TAT) agent in a comparative treatment study of [177Lu]Lu- versus [225Ac]Ac-DOTA-CCK-66. Methods: Treatment studies were performed (3 groups, n = 5, AR42J tumor-bearing 394-NOD SCID mice). Control group animals were injected with [68Ga]Ga-DOTA-CCK-66 (1.1 MBq, PET/CT imaging), while treatment group animals received a single dose of either [177Lu]Lu-DOTA-CCK-66 (37 MBq, radioligand therapy (RLT)) or [225Ac]Ac-DOTA-CCK-66 (37 kBq, TAT). All animals' tumor volume and body weight were monitored twice a week until end-point criteria were reached. Blood samples were evaluated (VetScan VS2, Abaxis) once mice were sacrificed. Results: Upon treatment, an initial decline in tumor volume, followed by a significantly delayed tumor growth of treated cohorts, was observed. Mean survival of 177Lu- as well as 225Ac-treated animals was increased by 3- (37 ± 3 d) and 4.5-fold (54 ± 6 d), respectively, when compared to non-treated animals (12 ± 3 d). Blood sample analysis did not indicate toxic side effects to the liver, kidney, or stomach upon 177Lu and 225Ac-treatment. Conclusion: We demonstrated a substantial therapeutic efficacy of 177Lu- and 225Ac-labeled DOTA-CCK-66. As expected, treatment with the latter resulted in the highest mean survival rates. These results indicate a high therapeutic potential of 225Ac-labeled DOTA-CCK-66 for TAT in MTC patient management. [ABSTRACT FROM AUTHOR]

Published
2025
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5. Evaluating [225Ac]Ac-FAPI-46 for the treatment of soft-tissue sarcoma in mice.

Author

Taddio, Marco F., Doshi, Suraj, Masri, Marwan, Jeanjean, Pauline, Hikmat, Firas, Gerlach, Alana, Nyiranshuti, Lea, Rosser, Ethan W., Schaue, Dorthe, Besserer-Offroy, Elie, Carlucci, Giuseppe, Radu, Caius G., Czernin, Johannes, Lückerath, Katharina, and Mona, Christine E.

Subjects
IMMUNE checkpoint proteins, TUMOR growth, PATIENT selection, FIBROSARCOMA, CANCER treatment
Abstract

Purpose: Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [225Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB. Methods: [68Ga]Ga- and [225Ac]Ac-FAPI-46 were tested in subcutaneous FAP+ FSA fibrosarcoma bearing C3H/Sed/Kam mice. The efficacy of up to three cycles of 60 kBq [225Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [225Ac]Ac-FAPI-46 and/or ICB was further compared in FAP-overexpressing FSA (FSA-F) tumors that were sensitive to ICB or rendered ICB-resistant by tumor-induction in the presence of Abatacept. Results: [225Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [225Ac]Ac-FAPI-46 and ICB resulted in growth delay in 55% of mice (6/11) and partial tumor regression in 18% (2/11) of mice. In FSA-F tumors with FAP overexpression, both [225Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [225Ac]Ac-FAPI-46 restored responsiveness to ICB, resulting in significant tumor regression and tumor-free survival of 56% of mice in the combination group up to 60 days post treatment. Conclusion: [225Ac]Ac-FAPI-46 efficacy is correlated with tumoral FAP expression levels and can restore responsiveness to PD-1 ICB. These data illustrate that careful patient selection based on target expression and rationally designed combination therapies are critically important to maximize the therapeutic impact of FAP-targeting radioligands. [ABSTRACT FROM AUTHOR]

Published
2024
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9. In Vitroand In VivoEvaluation of ABCG2 (BCRP) Inhibitors Derived from Ko143

Author

Zechner, Melanie, Castro Jaramillo, Claudia A., Zubler, Nadine S., Taddio, Marco F., Mu, Linjing, Altmann, Karl-Heinz, and Krämer, Stefanie D.

Abstract

Breast cancer resistance protein (BCRP, ABCG2) is an efflux transporter that plays a crucial role in multidrug resistance to antineoplastic drugs. Ko143, an analogue of the natural product fumitremorgin C, is a potent inhibitor of ABCG2 but is rapidly hydrolyzed to an inactive metabolite in vivo. To identify ABCG2 inhibitors with improved metabolic stability, we have assessed a series of Ko143 analogues for their ability to inhibit ABCG2-mediated transport in ABCG2-transduced MDCK II cells and determined the stability of the most potent compounds in liver microsomes. The most promising analogues were evaluated in vivoby positron emission tomography. In vitro, three of the tested analogues were potent ABCG2 inhibitors and stable in microsomes. In vivo, they increased the distribution of the ABCG2/ABCB1 substrate [11C]tariquidar to the brain both in wild-type (with Abcb1a/b transport blocked by tariquidar) and Abcb1a/b(−/−) mice. One analogue was more potent than Ko143 in both animal models.

Published
2023
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10. Synthesis and Structure-Affinity Relationship of Small Molecules for Imaging Human CD80 by Positron Emission Tomography

Author

Taddio, Marco F, Mu, Linjing, Castro Jaramillo, Claudia A, Bollmann, Tanja, Schmid, Dominik M, Muskalla, Lukas P, Gruene, Tim, Chiotellis, Aristeidis, Ametamey, Simon M, Schibli, Roger, Krämer, Stefanie D, University of Zurich, and Taddio, Marco F

Subjects
1313 Molecular Medicine, 3002 Drug Discovery, 610 Medicine & health, 10181 Clinic for Nuclear Medicine
Abstract

Journal of Medicinal Chemistry, 62 (17), ISSN:1520-4804, ISSN:0022-2623

Published
2019

11. In VivoImaging of Local Inflammation: Monitoring LPS-Induced CD80/CD86 Upregulation by PET

Author

Nicholas P. van der Meulen, Martin Béhé, Marco F. Taddio, Alain Blanc, Stefanie D. Krämer, Cornelia Halin, Roger Schibli, Zeynep Talip, Claudia Adrianna Castro Jaramillo, Peter Runge, and Claudia Keller

Subjects
Male, Lipopolysaccharides, Cancer Research, Biodistribution, Molecular imaging, Inflammation, chemical and pharmacologic phenomena, Flow cytometry, Abatacept, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Downregulation and upregulation, CD80, Positron Emission Tomography Computed Tomography, medicine, Animals, Co-stimulatory molecules, CD86, PET, Tissue Distribution, Radiology, Nuclear Medicine and imaging, Immune Checkpoint Inhibitors, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, Chemistry, hemic and immune systems, Molecular biology, Up-Regulation, Mice, Inbred C57BL, Copper Radioisotopes, Oncology, Models, Animal, B7-1 Antigen, B7-2 Antigen, Radiopharmaceuticals, medicine.symptom, Ex vivo, Research Article, 030215 immunology
Abstract

Purpose The co-stimulatory molecules CD80 and CD86 are upregulated on activated antigen-presenting cells (APC). We investigated whether local APC activation, induced by subcutaneous (s.c.) inoculation of lipopolysaccharides (LPS), can be imaged by positron emission tomography (PET) with CD80/CD86-targeting 64Cu-labelled abatacept. Procedures Mice were inoculated s.c. with extracellular-matrix gel containing either LPS or vehicle (PBS). Immune cell populations were analysed by flow cytometry and marker expression by RT-qPCR. 64Cu-NODAGA-abatacept distribution was analysed using PET/CT and ex vivo biodistribution. Results The number of CD80+ and CD86+ immune cells at the LPS inoculation site significantly increased a few days after inoculation. CD68 and CD86 expression were higher at the LPS than the PBS inoculation site, and CD80 was only increased at the LPS inoculation site. CTLA-4 was highest 10 days after LPS inoculation, when CD80/CD86 decreased again. A few days after inoculation, 64Cu-NODAGA-abatacept distribution to the inoculation site was significantly higher for LPS than PBS (4.2-fold). Co-administration of unlabelled abatacept or human immunoglobulin reduced tracer uptake. The latter reduced the number of CD86+ immune cells at the LPS inoculation site. Conclusions CD80 and CD86 are upregulated in an LPS-induced local inflammation, indicating invasion of activated APCs. 64Cu-NODAGA-abatacept PET allowed following APC activation over time., Molecular Imaging and Biology, 23, ISSN:1860-2002, ISSN:1536-1632

Published
2021
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13. Synthesis and Structure-Affinity Relationship of Small Molecules for Imaging Human CD80 by Positron Emission Tomography

Author

Aristeidis Chiotellis, Tim Gruene, Dominik Schmid, Marco F. Taddio, Roger Schibli, Claudia Adrianna Castro Jaramillo, Stefanie D. Krämer, Simon M. Ametamey, Lukas Muskalla, Linjing Mu, and Tanja Bollmann

Subjects
chemical and pharmacologic phenomena, Plasma protein binding, Mice, SCID, 01 natural sciences, Small Molecule Libraries, 03 medical and health sciences, chemistry.chemical_compound, Mice, In vivo, Positron Emission Tomography Computed Tomography, Drug Discovery, medicine, Animals, Humans, Binding site, 030304 developmental biology, 0303 health sciences, Binding Sites, medicine.diagnostic_test, Molecular Structure, Neoplasms, Experimental, Small molecule, In vitro, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, chemistry, Positron emission tomography, Biophysics, B7-1 Antigen, Molecular Medicine, Lead compound, CD80
Abstract

The costimulatory molecule CD80 is an early marker for immune activation. It is upregulated on activated antigen-presenting cells. We aimed at developing a tracer for imaging CD80 by positron emission tomography (PET). Novel CD80 ligands were synthesized and tested by SPR for affinity to human CD80 (hCD80) and displacement of endogenous ligands. Several compounds bound with one-digit nanomolar affinity to hCD80 and displaced CTLA-4 and CD28 at nanomolar concentrations. A structure-affinity relationship study revealed relevant moieties for strong affinity to hCD80 and positions for further modifications. Lead compound MT107 (7f) was radiolabeled with carbon-11. In vitro, [11C]MT107 showed specific binding to hCD80-positive tissue and high plasma protein binding. In vivo, [11C]MT107 accumulated in liver, gall bladder, and intestines but only scarcely in hCD80-positive xenografts. The unfavorable in vivo performance may result from high plasma protein binding and extensive biliary excretion.

Published
2019

15. Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the

Author

Marco F, Taddio, Linjing, Mu, Claudia, Keller, Roger, Schibli, and Stefanie D, Krämer

Subjects
Hepatobiliary Elimination, Mice, Metabolic Clearance Rate, Positron-Emission Tomography, Cyclosporine, Animals, Humans, Pharmacokinetics, Carbon Radioisotopes, Models, Theoretical, Radiopharmaceuticals, Carrier Proteins, Research Article
Abstract

Physiologically based pharmacokinetic modelling (PBPK) is a powerful tool to predict in vivo pharmacokinetics based on physiological parameters and data from in vivo studies and in vitro assays. In vivo PBPK modelling in laboratory animals by noninvasive imaging could help to improve the in vivo-in vivo translation towards human pharmacokinetics modelling. We evaluated the feasibility of PBPK modelling with PET data from mice. We used data from two of our PET tracers under development, [11C]AM7 and [11C]MT107. PET images suggested hepatobiliary excretion which was reduced after cyclosporine administration. We fitted the time-activity curves of blood, liver, gallbladder/intestine, kidney, and peripheral tissue to a compartment model and compared the resulting pharmacokinetic parameters under control conditions ([11C]AM7 n = 2; [11C]MT107, n = 4) and after administration of cyclosporine ([11C]MT107, n = 4). The modelling revealed a significant reduction in [11C]MT107 hepatobiliary clearance from 35.2 ± 10.9 to 17.1 ± 5.6 μl/min after cyclosporine administration. The excretion profile of [11C]MT107 was shifted from predominantly hepatobiliary (CLH/CLR = 3.8 ± 3.0) to equal hepatobiliary and renal clearance (CLH/CLR = 0.9 ± 0.2). Our results show the potential of PBPK modelling for characterizing the in vivo effects of transporter inhibition on whole-body and organ-specific pharmacokinetics.

Published
2018

17. Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice

Author

Taddio, Marco F; https://orcid.org/0000-0003-2477-5575, Mu, Linjing, Keller, Claudia, Schibli, Roger; https://orcid.org/0000-0002-1537-3833, Krämer, Stefanie D; https://orcid.org/0000-0002-0426-4340, Taddio, Marco F; https://orcid.org/0000-0003-2477-5575, Mu, Linjing, Keller, Claudia, Schibli, Roger; https://orcid.org/0000-0002-1537-3833, and Krämer, Stefanie D; https://orcid.org/0000-0002-0426-4340

Abstract

Physiologically based pharmacokinetic modelling (PBPK) is a powerful tool to predict pharmacokinetics based on physiological parameters and data from studies and assays. PBPK modelling in laboratory animals by noninvasive imaging could help to improve the translation towards human pharmacokinetics modelling. We evaluated the feasibility of PBPK modelling with PET data from mice. We used data from two of our PET tracers under development, [C]AM7 and [C]MT107. PET images suggested hepatobiliary excretion which was reduced after cyclosporine administration. We fitted the time-activity curves of blood, liver, gallbladder/intestine, kidney, and peripheral tissue to a compartment model and compared the resulting pharmacokinetic parameters under control conditions ([C]AM7 = 2; [C]MT107, = 4) and after administration of cyclosporine ([C]MT107, = 4). The modelling revealed a significant reduction in [C]MT107 hepatobiliary clearance from 35.2 ± 10.9 to 17.1 ± 5.6 l/min after cyclosporine administration. The excretion profile of [C]MT107 was shifted from predominantly hepatobiliary (CL/CL = 3.8 ± 3.0) to equal hepatobiliary and renal clearance (CL/CL = 0.9 ± 0.2). Our results show the potential of PBPK modelling for characterizing the effects of transporter inhibition on whole-body and organ-specific pharmacokinetics.

Published
2018

18. Synthesis and Structure–Affinity Relationship of Small Molecules for Imaging Human CD80 by Positron Emission Tomography

Author

Taddio, Marco F., Mu, Linjing, Castro Jaramillo, Claudia A., Bollmann, Tanja, Schmid, Dominik M., Muskalla, Lukas P., Gruene, Tim, Chiotellis, Aristeidis, Ametamey, Simon M., Schibli, Roger, and Krämer, Stefanie D.

Abstract

The costimulatory molecule CD80 is an early marker for immune activation. It is upregulated on activated antigen-presenting cells. We aimed at developing a tracer for imaging CD80 by positron emission tomography (PET). Novel CD80 ligands were synthesized and tested by SPR for affinity to human CD80 (hCD80) and displacement of endogenous ligands. Several compounds bound with one-digit nanomolar affinity to hCD80 and displaced CTLA-4 and CD28 at nanomolar concentrations. A structure–affinity relationship study revealed relevant moieties for strong affinity to hCD80 and positions for further modifications. Lead compound MT107 (7f) was radiolabeled with carbon-11. In vitro, [11C]MT107 showed specific binding to hCD80-positive tissue and high plasma protein binding. In vivo, [11C]MT107 accumulated in liver, gall bladder, and intestines but only scarcely in hCD80-positive xenografts. The unfavorable in vivo performance may result from high plasma protein binding and extensive biliary excretion.

Published
2024
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19. Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice

Author

Taddio, Marco F., Mu, Linjing, Keller, Claudia, Schibli, Roger, and Krämer, Stefanie-Dorothea

Subjects
3. Good health
Abstract

Physiologically based pharmacokinetic modelling (PBPK) is a powerful tool to predict in vivo pharmacokinetics based on physiological parameters and data from in vivo studies and in vitro assays. In vivo PBPK modelling in laboratory animals by noninvasive imaging could help to improve the in vivo-in vivo translation towards human pharmacokinetics modelling. We evaluated the feasibility of PBPK modelling with PET data from mice. We used data from two of our PET tracers under development, [11C]AM7 and [11C]MT107. PET images suggested hepatobiliary excretion which was reduced after cyclosporine administration. We fitted the time-activity curves of blood, liver, gallbladder/intestine, kidney, and peripheral tissue to a compartment model and compared the resulting pharmacokinetic parameters under control conditions ([11C]AM7 n=2; [11C]MT107, n=4) and after administration of cyclosporine ([11C]MT107, n=4). The modelling revealed a significant reduction in [11C]MT107 hepatobiliary clearance from 35.2±10.9 to 17.1±5.6 μl/min after cyclosporine administration. The excretion profile of [11C]MT107 was shifted from predominantly hepatobiliary (CLH/CLR = 3.8±3.0) to equal hepatobiliary and renal clearance (CLH/CLR = 0.9±0.2). Our results show the potential of PBPK modelling for characterizing the in vivo effects of transporter inhibition on whole-body and organ-specific pharmacokinetics., Contrast Media & Molecular Imaging, 2018, ISSN:1555-4317, ISSN:1555-4309

20. Synthesis and Structure-Affinity Relationship of Small Molecules for Imaging Human CD80 by Positron Emission Tomography.

Author

Taddio MF, Mu L, Castro Jaramillo CA, Bollmann T, Schmid DM, Muskalla LP, Gruene T, Chiotellis A, Ametamey SM, Schibli R, and Krämer SD

Subjects
Animals, Binding Sites, Humans, Mice, Mice, SCID, Molecular Structure, Neoplasms, Experimental diagnostic imaging, Small Molecule Libraries chemical synthesis, B7-1 Antigen analysis, Positron Emission Tomography Computed Tomography, Small Molecule Libraries chemistry
Abstract

The costimulatory molecule CD80 is an early marker for immune activation. It is upregulated on activated antigen-presenting cells. We aimed at developing a tracer for imaging CD80 by positron emission tomography (PET). Novel CD80 ligands were synthesized and tested by SPR for affinity to human CD80 (hCD80) and displacement of endogenous ligands. Several compounds bound with one-digit nanomolar affinity to hCD80 and displaced CTLA-4 and CD28 at nanomolar concentrations. A structure-affinity relationship study revealed relevant moieties for strong affinity to hCD80 and positions for further modifications. Lead compound MT107 ( 7f ) was radiolabeled with carbon-11. In vitro, [ 11 C]MT107 showed specific binding to hCD80-positive tissue and high plasma protein binding. In vivo, [ 11 C]MT107 accumulated in liver, gall bladder, and intestines but only scarcely in hCD80-positive xenografts. The unfavorable in vivo performance may result from high plasma protein binding and extensive biliary excretion.

Published
2019
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