Modular Medical Imaging Agents Based on Azide–Alkyne Huisgen Cycloadditions: Synthesis and Pre‐Clinical Evaluation of <sup>18</sup>F‐Labeled PSMA‐Tracers for Prostate Cancer Imaging

Böhmer, Verena I.; Szymański, Wiktor; Berg, Keimpe-Oeds van den; Mulder, Chantal; Kobauri, Piermichele; Helbert, Hugo; Born, Dion van der; Reeβing, Friederike; Huizing, Anja; Klopstra, Marten; Samplonius, Douwe F.; Antunes, Inês Farinha; Sijbesma, J. W. A.; Luurtsema, Gert; Helfrich, Wijnand; Visser, T.; Feringa, Ben L.; Elsinga, Philip H.

doi:10.1002/chem.202001795

Cited by 18 publications

(18 citation statements)

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“… 24 In addition, Böhmer et al developed and characterized a copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) based PSMA ligand for PET imaging called [ 18 F]PSMA-MIC01. 29 This CuAAC-based ligand showed specific tumor uptake in LNCaP xenografts (11.7 ± 4.2%ID/g, 1 h p.i.) with only minor nonspecific uptake in other organs.…”

Section: Discussionmentioning

confidence: 92%

Strain-Promoted Azide–Alkyne Cycloaddition-Based PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection of Prostate Cancer

et al. 2021

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Strain-promoted azide–alkyne cycloaddition (SPAAC) is a straightforward and multipurpose conjugation strategy. The use of SPAAC to link different functional elements to prostate-specific membrane antigen (PSMA) ligands would facilitate the development of a modular platform for PSMA-targeted imaging and therapy of prostate cancer (PCa). As a first proof of concept for the SPAAC chemistry platform, we synthesized and characterized four dual-labeled PSMA ligands for intraoperative radiodetection and fluorescence imaging of PCa. Ligands were synthesized using solid-phase chemistry and contained a chelator for 111 In or 99m Tc labeling. The fluorophore IRDye800CW was conjugated using SPAAC chemistry or conventional N -hydroxysuccinimide (NHS)–ester coupling. Log D values were measured and PSMA specificity of these ligands was determined in LS174T-PSMA cells. Tumor targeting was evaluated in BALB/c nude mice with subcutaneous LS174T-PSMA and LS174T wild-type tumors using μSPECT/CT imaging, fluorescence imaging, and biodistribution studies. SPAAC chemistry increased the lipophilicity of the ligands (log D range: −2.4 to −4.4). In vivo , SPAAC chemistry ligands showed high and specific accumulation in s.c. LS174T-PSMA tumors up to 24 h after injection, enabling clear visualization using μSPECT/CT and fluorescence imaging. Overall, no significant differences between the SPAAC chemistry ligands and their NHS-based counterparts were found (2 h p.i., p > 0.05), while 111 In-labeled ligands outperformed the 99m Tc ligands. Here, we demonstrate that our newly developed SPAAC-based PSMA ligands show high PSMA-specific tumor targeting. The use of click chemistry in PSMA ligand development opens up the opportunity for fast, efficient, and versatile conjugations of multiple imaging moieties and/or drugs.

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Section: Discussionmentioning

confidence: 92%

Strain-Promoted Azide–Alkyne Cycloaddition-Based PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection of Prostate Cancer

et al. 2021

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“…developed and characterized a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) based PSMA ligand for PET imaging called [ 18 F]PSMA-MIC01 [34]. This CuAAC-based ligand showed speci c tumor uptake in LNCaP xenografts (11.7 ± 4.2 %ID/g, 1 h p.i.)…”

Section: Discussionmentioning

confidence: 99%

Strain-Promoted Azide-Alkyne Cycloaddition-Based PSMA-Targeting Ligands For Multimodal Intraoperative Tumor Detection of Prostate Cancer

Derks

Rijpkema

Amatdjais-Groenen

et al. 2021

Preprint

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Purpose: Strain-promoted azide-alkyne cycloaddition (SPAAC) is a straightforward and multipurpose conjugation strategy. Use of SPAAC to link different functional elements to prostate specific membrane antigen (PSMA) ligands would facilitate the development of a modular platform for PSMA-targeted imaging and therapy of prostate cancer (PCa). As a first proof-of-concept for the SPAAC chemistry platform we synthesized and characterized four dual-labeled PSMA ligands for intraoperative radiodetection and fluorescence imaging of PCa. Methods: Ligands were synthesized using solid phase chemistry and contained a chelator for 111In or 99mTc labeling. The fluorophore IRDye800CW was conjugated using SPAAC chemistry or conventional N-hydroxysuccinimide (NHS)-ester coupling. LogD values were measured and PSMA-specificity of these ligands was determined in LS174T-PSMA cells. Tumor targeting was evaluated in BALB/c nude mice with subcutaneous LS174T-PSMA and LS174T wildtype tumors using µSPECT/CT imaging, fluorescence imaging, and biodistribution studies. Results: SPAAC chemistry increased lipophilicity of the ligands (range LogD: -2.4 to -4.4). In vivo, SPAAC chemistry ligands showed high and specific accumulation in s.c. LS174T-PSMA tumors up to 24 hours after injection, enabling clear visualization using µSPECT/CT and fluorescence imaging. Overall, no significant differences between the SPAAC chemistry ligands and their NHS-based counterparts were found (2 h p.i., p > 0.05), while 111In-labeled ligands outperformed the 99mTc ligands. Conclusion: Here we demonstrate that our newly developed SPAAC-based PSMA ligands show high PSMA-specific tumor targeting. Use of click-chemistry in PSMA ligand development opens up the opportunity for fast, efficient and versatile conjugations of multiple imaging moieties and/or drugs.

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“…Several PSMA derivatives have already been radiolabeled following this technique, two of which look promising, 29,30 showing uptake and tumor-to-background comparable or even better than [68Ga]PSMA-11.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and automated fluorine‐18 radiolabeling of new PSMA‐617 derivatives with a CuAAC radiosynthetic approach

Iannone

Stucchi

Turolla

et al. 2022

Labelled Comp Radiopharmac

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In the last decade, the development of new radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research, especially focusing on the prostate‐specific membrane antigen (PSMA), an antigen which is upregulated in prostate, as well as in other tumor cells. A large variety of PSMA ligands have been radiolabeled, to date. Among the various derivatives, PSMA‐617 resulted to be one of the most interesting in terms of interaction with the antigen and clinical properties, and its lutetium‐177 labeled version has recently been approved by regulatory agencies for therapeutic purposes. For this reasons, the radiolabeling with fluorine‐18 of a PSMA‐617 derivative might be of interest. Beside other methodologies to radiolabel macromolecules with fluorine‐18, the “click‐chemistry” approach resulted to be very useful, and the copper‐catalyzed azide‐alkyne cycloaddition (CuAAC) is considered one of most efficient and reliable. This paper proposes the synthesis of a suitable precursor for the radiolabeling with fluorine‐18 of a new PSMA‐617 derivative. The whole radiosynthetic procedure has been fully automated, and the final product, which proved to be stable in plasma, has been obtained with radiochemical yield and purity suitable for subsequent preclinical studies.

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Modular Medical Imaging Agents Based on Azide–Alkyne Huisgen Cycloadditions: Synthesis and Pre‐Clinical Evaluation of ¹⁸F‐Labeled PSMA‐Tracers for Prostate Cancer Imaging

Cited by 18 publications

References 74 publications

Strain-Promoted Azide–Alkyne Cycloaddition-Based PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection of Prostate Cancer

Strain-Promoted Azide–Alkyne Cycloaddition-Based PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection of Prostate Cancer

Strain-Promoted Azide-Alkyne Cycloaddition-Based PSMA-Targeting Ligands For Multimodal Intraoperative Tumor Detection of Prostate Cancer

Synthesis and automated fluorine‐18 radiolabeling of new PSMA‐617 derivatives with a CuAAC radiosynthetic approach

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Modular Medical Imaging Agents Based on Azide–Alkyne Huisgen Cycloadditions: Synthesis and Pre‐Clinical Evaluation of 18F‐Labeled PSMA‐Tracers for Prostate Cancer Imaging

Cited by 18 publications

References 74 publications

Strain-Promoted Azide–Alkyne Cycloaddition-Based PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection of Prostate Cancer

Strain-Promoted Azide–Alkyne Cycloaddition-Based PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection of Prostate Cancer

Strain-Promoted Azide-Alkyne Cycloaddition-Based PSMA-Targeting Ligands For Multimodal Intraoperative Tumor Detection of Prostate Cancer

Synthesis and automated fluorine‐18 radiolabeling of new PSMA‐617 derivatives with a CuAAC radiosynthetic approach

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Modular Medical Imaging Agents Based on Azide–Alkyne Huisgen Cycloadditions: Synthesis and Pre‐Clinical Evaluation of ¹⁸F‐Labeled PSMA‐Tracers for Prostate Cancer Imaging