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

被引：18

作者：

Bohmer, Verena I. ^{[1
,2
]}

Szymanski, Wiktor ^{[1
,2
]}

van den Berg, Keimpe-Oeds ^{[1
]}

Mulder, Chantal ^{[1
]}

Kobauri, Piermichele ^{[2
]}

Helbert, Hugo ^{[1
,2
]}

van Der Born, Dion ^{[3
]}

Reessing, Friederike ^{[1
,2
]}

Huizing, Anja ^{[1
,2
]}

Klopstra, Marten ^{[4
]}

Samplonius, Douwe F. ^{[1
]}

Antunes, Ines F. ^{[1
]}

Sijbesma, Jurgen W. A. ^{[1
]}

Luurtsema, Gert ^{[1
]}

Helfrich, Wijnand ^{[1
]}

Visser, Ton J. ^{[4
]}

Feringa, Ben L. ^{[2
]}

Elsinga, Philip H. ^{[1
]}

机构：

[1] Univ Groningen, Univ Med Ctr Groningen, Dept Nucl Med & Mol Imaging, Dept Radiol,Dept Surg Oncol, Hanzepl 1, NL-9713 GZ Groningen, Netherlands

[2] Univ Groningen, Stratingh Inst Chem, Nijenborgh 4, NL-9747 AF Groningen, Netherlands

[3] FutureChemistry, Toernooiveld 100, NL-6525 EC Nijmegen, Netherlands

[4] Syncom, Kadijk 3, NL-9747 AT Groningen, Netherlands

来源：

CHEMISTRY-A EUROPEAN JOURNAL | 2020年 / 26卷 / 47期

关键词：

cancer; click chemistry; cycloadditions; imaging agents; positron emission tomography; GLUTAMATE-CARBOXYPEPTIDASE-II; MEMBRANE ANTIGEN; CLICK CHEMISTRY; CLINICAL TRANSLATION; PET; INHIBITORS; DESIGN; LIGATION; THERAPY; IMPACT;

D O I：

10.1002/chem.202001795

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Since the seminal contribution of Rolf Huisgen to develop the [3+2] cycloaddition of 1,3-dipolar compounds, its azide-alkyne variant has established itself as the key step in numerous organic syntheses and bioorthogonal processes in materials science and chemical biology. In the present study, the copper(I)-catalyzed azide-alkyne cycloaddition was applied for the development of a modular molecular platform for medical imaging of the prostate-specific membrane antigen (PSMA), using positron emission tomography. This process is shown from molecular design, through synthesis automation andin vitrostudies, all the way to pre-clinicalin vivoevaluation of fluorine-18- labeled PSMA-targeting 'F-PSMA-MIC' radiotracers (t(1/2)=109.7 min). Pre-clinical data indicate that the modular PSMA-scaffold has similar binding affinity and imaging properties to the clinically used [Ga-68]PSMA-11. Furthermore, we demonstrated that targeting the arene-binding in PSMA, facilitated through the [3+2]cycloaddition, can improve binding affinity, which was rationalized by molecular modeling. The here presented PSMA-binding scaffold potentially facilitates easy coupling to other medical imaging moieties, enabling future developments of new modular imaging agents.

引用

页码：10871 / 10881

页数：11

共 80 条

[71] Design of Highly Potent Urea-Based, Exosite-Binding Inhibitors Selective for Glutamate Carboxypeptidase II [J].