Synthesis and labeling of a squaric acid containing PSMA-inhibitor coupled to AAZTA5 for versatile labeling with 44Sc, 64Cu, 68Ga and 177Lu

Greifenstein, Lukas; Grus, Tilmann; Nagel, Johannes; Sinnes, Jean Phillip; Rösch, Frank

doi:10.1016/j.apradiso.2019.108867

Cited by 24 publications

(43 citation statements)

References 29 publications

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“…SA is the main component of the linker system forming a squaramide unit and accordingly substitutes the heterocyclic nitrogen moieties in the structures reported by the Heidelberg group (Lindner et al 2018;Loktev et al 2019;Loktev et al 2018). In recent works from our group, SA has shown good results, both in chemistry and physiologically, as a linker unit coupled with PSMA inhibitors (Greifenstein et al 2020;Greifenstein et al 2019). The asymmetrically substituted squaramide unit in the target compounds was efficiently installed with SADE, relying on the latter's elegant pH-dependent chemistry and selectivity for primary amines.…”

Section: Discussionmentioning

confidence: 99%

“…The use of SA as a linker unit between a chelator-biomolecule conjugate as a radiopharmaceutical was demonstrated using DFO and conjugation on a peptide to complex iron and using DFOsquaric acid coupled to antibodies for complexing zirconium-89 (Rudd et al 2016;Yoganathan et al 2011). Recently, our group published the usage of SA as a linker forming a radiotracer with the bifunctional hybrid chelator AAZTA 5 coupled to a PSMA inhibitor unit (KuE) and evaluated those AAZTA 5 .SA.PSMA conjugate with various radionuclides such as scandium-44, copper-64, gallium-68 and lutetium-177 (Greifenstein et al 2019). Additionally, we indicate a second feature of SA beyond coupling chemistry.…”

Section: Introductionmentioning

confidence: 99%

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Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

Moon

Elvas

Vliegen

et al. 2020

EJNMMI radiopharm. chem.

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Background: Fibroblast activation protein (FAP) is a proline selective serine protease that is overexpressed in tumor stroma and in lesions of many other diseases that are characterized by tissue remodeling. In 2014, a most potent FAP-inhibitor (referred to as UAMC1110) with low nanomolar FAP-affinity and high selectivity toward related enzymes such as prolyl oligopeptidase (PREP) and the dipeptidyl-peptidases (DPPs): DPP4, DPP8/9 and DPP2 were developed. This inhibitor has been adopted recently by other groups to create radiopharmaceuticals by coupling bifunctional chelatorlinker systems. Here, we report squaric acid (SA) containing bifunctional DATA 5m and DOTA chelators based on UAMC1110 as pharmacophor. The novel radiopharmaceuticals DOTA.SA.FAPi and DATA 5m .SA.FAPi with their non-radioactive derivatives were characterized for in vitro inhibitory efficiency to FAP and PREP, respectively and radiochemical investigated with gallium-68. Further, first proof-ofconcept in vivo animal study followed by ex vivo biodistribution were determined with [ 68 Ga]Ga-DOTA.SA.FAPi. Results: [ 68 Ga]Ga-DOTA.SA.FAPi and [ 68 Ga]Ga-DATA 5m .SA.FAPi showed high complexation > 97% radiochemical yields after already 10 min and high stability over a period of 2 h. Affinity to FAP of DOTA.SA.FAPi and DATA 5m .SA.FAPi and its nat Ga and nat Lu-labeled derivatives were excellent resulting in low nanomolar IC 50 values of 0.7-1.4 nM. Additionally, all five compounds showed low affinity for the related protease PREP (high IC 50 with 1.7-8.7 μM). First proof-of-principle in vivo PET-imaging animal studies of the [ 68 Ga]Ga-DOTA.SA.FAPi precursor in a HT-29 human colorectal cancer xenograft mouse model indicated promising results with high accumulation in tumor (SUV mean of 0.75) and low background signal. Ex vivo biodistribution showed highest uptake in tumor (5.2%ID/g) at 60 min post injection with overall low uptake in healthy tissues.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

Moon

Elvas

Vliegen

et al. 2020

EJNMMI radiopharm. chem.

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“…The coupling of squaric acid to the terminal carboxyl group and the subsequent binding to the FAP inhibitor was performed in the same way as for the previously described DATA 5m .SA.FAPi [24]. Figure 1 shows the synthesis route of AAZTA 5 .SA.FAPi, following the protocol of Sinnes et al and Greifenstein et al [44,45]. [44,45]; (**) as reported [24].…”

Section: Synthesis Of Chelator Conjugatesmentioning

confidence: 99%

“…Figure 1 shows the synthesis route of AAZTA 5 .SA.FAPi, following the protocol of Sinnes et al and Greifenstein et al [44,45]. [44,45]; (**) as reported [24]. DOTA.SA.FAPi was synthesized as previously described [24].…”

Section: Synthesis Of Chelator Conjugatesmentioning

confidence: 99%

In Vitro Evaluation of the Squaramide-Conjugated Fibroblast Activation Protein Inhibitor-Based Agents AAZTA5.SA.FAPi and DOTA.SA.FAPi

et al. 2021

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Recently, the first squaramide-(SA) containing FAP inhibitor-derived radiotracers were introduced. DATA5m.SA.FAPi and DOTA.SA.FAPi with their non-radioactive complexes showed high affinity and selectivity for FAP. After a successful preclinical study with [68Ga]Ga-DOTA.SA.FAPi, the first patient studies were realized for both compounds. Here, we present a new squaramide-containing compound targeting FAP, based on the AAZTA5 chelator 1,4-bis-(carboxylmethyl)-6-[bis-(carboxymethyl)-amino-6-pentanoic-acid]-perhydro-1,4-diazepine. For this molecule (AAZTA5.SA.FAPi), complexation with radionuclides such as gallium-68, scandium-44, and lutetium-177 was investigated, and the in vitro properties of the complexes were characterized and compared with those of DOTA.SA.FAPi. AAZTA5.SA.FAPi and its derivatives labelled with non-radioactive isotopes demonstrated similar excellent inhibitory potencies compared to the previously published SA.FAPi ligands, i.e., sub-nanomolar IC50 values for FAP and high selectivity indices over the serine proteases PREP and DPPs. Labeling with all three radiometals was easier and faster with AAZTA5.SA.FAPi compared to the corresponding DOTA analogue at ambient temperature. Especially, scandium-44 labeling with the AAZTA derivative resulted in higher specific activities. Both DOTA.SA.FAPi and AAZTA5.SA.FAPi showed sufficiently high stability in different media. Therefore, these FAP inhibitor agents could be promising for theranostic approaches targeting FAP.

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“…In recent works from our group, SA has shown good results, both in chemistry and physiologically, as a linker unit coupled with PSMA inhibitors. [35,36] DOTA.SA.FAPi and DATA 5m .SA.FAPi showed very good in vitro complexations of 68 Ga and a very high stability in different media of more than 95% intact conjugate. In general, the hybrid chelator DATA 5m shows a quantitative complexation under mild conditions and is therefore very well suited to label temperature sensitive target molecules with radiometals.…”

Section: Resultsmentioning

confidence: 91%

Targeting fibroblast activation protein (FAP): Next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

Moon

Elvas

Vliegen

et al. 2020

Preprint

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Background Fibroblast activation protein (FAP) is a proline selective serine protease that is overexpressed in tumor stroma and in lesions of many other diseases that are characterized by tissue remodeling. In 2014, a most potent FAP-inhibitor (referred to as UAMC1110) with low nanomolar FAP-affinity and high selectivity toward related enzymes such as prolyl oligopeptidase (PREP) and the dipeptidyl-peptidases (DPPs): DPP4, DPP8/9 and DPP2 were developed. This inhibitor has been adopted recently by other groups to create radiopharmaceuticals by coupling bifunctional chelator-linker systems. Here, we report squaric acid containing bifunctional DATA5m and DOTA chelators relied on UAMC1110. Results The radiopharmaceuticals DOTA.SA.FAPi and DATA5m.SA.FAPi were synthesized, labeled with gallium-68 and further characterized for in vitro stability, inhibitory efficiency, in vivo targeting properties and ex vivo biodistribution. [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DATA5m.SA.FAPi showed high complexation after already 10 minutes and high stability over a period of 2 h. Affinity to FAP of DOTA.SA.FAPi and its natGa and natLu-labeled derivatives were in low nanomolar range. Comparable results were obtained for DATA5m.SA.FAPi and its natGa analogue. Additionally, all five compounds showed low affinity for the related protease PREP (high µM range). First proof-of-principle in vivo PET-imaging animal studies of the [68Ga]Ga-DOTA.SA.FAPi precursor in a HT-29 human colorectal cancer xenograft mouse model indicated promising results with high accumulation in tumor and low background signal. Ex vivo biodistribution showed high tumor uptake at 60 min post injection with overall low uptake in healthy tissues. Conclusion In this work, novel PET radiotracers targeting fibroblast activation protein (FAP) were synthesized and biochemically investigated. Critical substructures of the novel compounds are a squaramide linker unit derived from the basic motif of squaric acid, DOTA and DATA5m bifunctional chelators and a FAP-targeting moiety. In conclusion, these new FAP-ligands appear promising, both for further research and development as well as for first human application.

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Synthesis and labeling of a squaric acid containing PSMA-inhibitor coupled to AAZTA5 for versatile labeling with 44Sc, 64Cu, 68Ga and 177Lu

Cited by 24 publications

References 29 publications

Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

In Vitro Evaluation of the Squaramide-Conjugated Fibroblast Activation Protein Inhibitor-Based Agents AAZTA5.SA.FAPi and DOTA.SA.FAPi

Targeting fibroblast activation protein (FAP): Next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators

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