Synthesis, Preclinical Evaluation, and First-in-Human PET Study of Quinoline-Containing PSMA Tracers with Decreased Renal Excretion

Zhang, Xiaojun; Wu, Yitian; Zeng, Qi; Xie, Tianxin; Yao, Shulin; Zhang, Jinming; Cui, Mengchao

doi:10.1021/acs.jmedchem.1c00117

Cited by 20 publications

(18 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, a lipophilic character of the tracer can increase nonspecific uptake in other organs. 20 , 22 − 24 , 28 In the case of PSMA ligands, higher ligand lipophilicity of PSMA-I&T-based ligands led to an increase in tumor uptake in LNCaP xenografts. 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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

show abstract

“…aromatics such as in dibenzocyclooctene), is prone to increase the fraction of slow hepatobiliary clearance [29]. In addition, the study of Zhang et al showed that addition of lipophilic quinoline groups in PSMA ligand [ 18 F]DCFPyl led to a large increase in liver accumulation in mice, primates and PCa patients [33].…”

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

View full text Add to dashboard Cite

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.

show abstract

“…Recently, Vaidyanathan et al demonstrated further improvements in the biodistribution and pharmacokinetic profile by adding a guanidino group to the aromatic ring of the inhibitor [82]. In addition, modifications with quinolone derivatives appear advantageous in diagnostic tracers and could potentially serve as templates for future therapeutic approaches [83].…”

Section: Linkers and Chelatorsmentioning

confidence: 99%

PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives

Fakiri

Geis

Ayada

et al. 2021

Cancers

View full text Add to dashboard Cite

Prostate cancer (PC) is the second most common cancer among men, with 1.3 million yearly cases worldwide. Among those cancer-afflicted men, 30% will develop metastases and some will progress into metastatic castration-resistant prostate cancer (mCRPC), which is associated with a poor prognosis and median survival time that ranges from nine to 13 months. Nevertheless, the discovery of prostate specific membrane antigen (PSMA), a marker overexpressed in the majority of prostatic cancerous tissue, revolutionised PC care. Ever since, PSMA-targeted radionuclide therapy has gained remarkable international visibility in translational oncology. Furthermore, on first clinical application, it has shown significant influence on therapeutic management and patient care in metastatic and hormone-refractory prostate cancer, a disease that previously had remained immedicable. In this article, we provide a general overview of the main milestones in the development of ligands for PSMA-targeted radionuclide therapy, ranging from the firstly developed monoclonal antibodies to the current state-of-the-art low molecular weight entities conjugated with various radionuclides, as well as potential future efforts related to PSMA-targeted radionuclide therapy.

show abstract

Synthesis, Preclinical Evaluation, and First-in-Human PET Study of Quinoline-Containing PSMA Tracers with Decreased Renal Excretion

Cited by 20 publications

References 49 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

PSMA-Targeting Radiopharmaceuticals for Prostate Cancer Therapy: Recent Developments and Future Perspectives

Contact Info

Product

Resources

About