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 and in vitro studies, all the way to pre‐clinical in vivo evaluation of fluorine‐18‐ labeled PSMA‐targeting ‘F‐PSMA‐MIC’ radiotracers (t1/2=109.7 min). Pre‐clinical data indicate that the modular PSMA‐scaffold has similar binding affinity and imaging properties to the clinically used [68Ga]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.

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The published article is lacking ah ighly relevantr eference regarding clickable PSMAligandsw ith alkyne-moiety.H ence,t he authors would like to acknowledge the work by Kelly et al. (2017), who already presented six alkyne-functionalized PSMA binding motifs,t hree triazolyl and three triazolylmethoxy variants with subsequent successful radiolabeling with [ 18 F]fluoro-azide using azido-ethylene synthons. The authors would like to apologize for the oversight. The following is the relevant section of the paper with amendments highlightedi n italics: Results and DiscussionDesign of F-PSMA-MIC01.PSMA is aw ell-characterized target in structure-activity-relationship (SAR) studies. [53] The naturalf unctiono ft his membrane zinc-metallopeptidase is to cleave glutamate from N-acetyl-l-aspartyl-l-glutamate. This antigen has ag lutamate-favoring S1'pocket [54][55][56] and SAR analysis revealed an adaptive, hydrophobic-favoring S1-pocket, createdb ya na rginine patch formed by Arg463, Arg534 and Arg536 that can accommodate av ariety of inhibitors. [57] PSMA-targeting compounds with the Glu-urea-Lys motif bind to the S1-hydrophobic pocket and the S1'-pocket, as well as to the zinc ions. [57] Interestingly,i tw as found that the presence of a1 ,2,3-triazole motif in PSMA inhibitors enablesb inding to an additional arene-bindings ite, whichh as inspired us to use this moiety in developing PSMA-targeting radiotracers with high affinity. [57] For this purpose, we designed am odulars ynthesis approach for PSMA-targeting radiotracers which can potentially be applied to different imaging modalities by adapting the existing Glu-urea-Lys motif [57] so that it is able to undergo the Huisgen [3 + + 2]-cycloaddition. Even further,i n2 017i tw as already shown that clickable PSMA-inhibitors are valuable precursors for potent PET imaging agents. [C, 52] Here, we introduce the radiotracer [ 18 F]PSMA-MIC01 (Figure 2A), which is formed by alkyne-Glu-urea-Lys motif and PET-radionuclide 18 F, spacedf rom the 1,2,3-triazoleb y adiethylene-glycol-linker,which was shown to display the right linker length. [51] Compared to the previously published alkyne-PSMA binding motif, [C] our PSMA-binding motif modifies the lysine of the existing Glu-urea-Lys motif to ab enzamide instead of ap henylurea. Additionally,t he synthonu sedf or the [ 18 F]fluorinations is based on azidodiethylene-glycol instead of the azido-ethylene synthon used by Kelly et al. [C] [c] J.