Multivalent Probes in Molecular Imaging: Reality or Future?

Böhmer, Verena I.; Szymański, Wiktor; Feringa, Ben L.; Elsinga, Philip H.

doi:10.1016/j.molmed.2020.12.006

Cited by 26 publications

(25 citation statements)

References 99 publications

(174 reference statements)

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“…We now report the successful application of the novel, improved 68 Ga-labeled trimerized αvβ6-integrin selective nonapeptide 68 Ga-Trivehexin (Fig. 1) for imaging of human carcinomas, thus transforming the concept of multivalent molecular imaging probes from a future vision [41] into clinical reality.…”

Section: Introductionmentioning

confidence: 99%

PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the “Cancer Integrin” αvβ6 with Ga-68-Trivehexin

Quigley

Steiger

Hoberück

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose To develop a new probe for the αvβ6-integrin and assess its potential for PET imaging of carcinomas. Methods Ga-68-Trivehexin was synthesized by trimerization of the optimized αvβ6-integrin selective cyclic nonapeptide Tyr2 (sequence: c[YRGDLAYp(NMe)K]) on the TRAP chelator core, followed by automated labeling with Ga-68. The tracer was characterized by ELISA for activities towards integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1, as well as by cell binding assays on H2009 (αvβ6-positive) and MDA-MB-231 (αvβ6-negative) cells. SCID-mice bearing subcutaneous xenografts of the same cell lines were used for dynamic (90 min) and static (75 min p.i.) µPET imaging, as well as for biodistribution (90 min p.i.). Structure–activity-relationships were established by comparison with the predecessor compound Ga-68-TRAP(AvB6)3. Ga-68-Trivehexin was tested for in-human PET/CT imaging of HNSCC, parotideal adenocarcinoma, and metastatic PDAC. Results Ga-68-Trivehexin showed a high αvβ6-integrin affinity (IC50 = 0.047 nM), selectivity over other subtypes (IC50-based factors: αvβ8, 131; αvβ3, 57; α5β1, 468), blockable uptake in H2009 cells, and negligible uptake in MDA-MB-231 cells. Biodistribution and preclinical PET imaging confirmed a high target-specific uptake in tumor and a low non-specific uptake in other organs and tissues except the excretory organs (kidneys and urinary bladder). Preclinical PET corresponded well to in-human results, showing high and persistent uptake in metastatic PDAC and HNSCC (SUVmax = 10–13) as well as in kidneys/urine. Ga-68-Trivehexin enabled PET/CT imaging of small PDAC metastases and showed high uptake in HNSCC but not in tumor-associated inflammation. Conclusions Ga-68-Trivehexin is a valuable probe for imaging of αvβ6-integrin expression in human cancers.

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Section: Introductionmentioning

confidence: 99%

PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the “Cancer Integrin” αvβ6 with Ga-68-Trivehexin

Quigley

Steiger

Hoberück

et al. 2021

Eur J Nucl Med Mol Imaging

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“…In order to exploit the multimer effect to achieve a higher target affinity, enhanced uptake, and longer retention [41], we reasoned that increasing the intrinsic hydrophilicity of c[FRGDLAFp(NMe)K] should both accelerate blood clearance and reduce non-specific uptake of the corresponding trimers. An exchange of both phenylalanines by tyrosines appeared to be a convenient and simple strategy, yet at the risk of considerably lowering target affinity and selectivity which, fortunately, did not occur.…”

Section: Strategy For Optimization Of Biokineticsmentioning

confidence: 99%

“…A 68 Ga-labeled TRAP trimer thereof, referred to as 68 Ga-TRAP(AvB6)3 (Figure 1), showed a very unfavorable biodistribution [17] and required further optimization. We now report the successful application of the novel, improved 68 Ga-labeled trimerized αvβ6-integrin selective nonapeptide 68 Ga-Trivehexin (Figure 1) for imaging of human carcinomas, thus transforming the concept of multivalent molecular imaging probes from a future vision [41] into clinical reality.…”

Section: Introductionmentioning

confidence: 99%

PET/CT Imaging of Head-and-Neck and Pancreatic Cancer in Humans by Targeting the "Cancer Integrin" αvβ6 with Ga-68-Trivehexin

Quigley

Steiger

Hoberück³

et al. 2021

Preprint

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PurposeTo develop a new probe for the αvβ6-integrin and assess its potential for PET imaging of carcinomas.MethodsGa-68-Trivehexin was synthesized by trimerization of an optimized αvβ6-integrin selective cyclicnonapeptide on the TRAP chelator core and automated labeling with Ga-68. The tracer wascharacterized by ELISA for activities towards integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1, as well asby cell binding assays on H2009 (αvβ6-positive) and MDA-MB-231 (αvβ6-negative) cells. SCID micebearing subcutaneous xenografts of the same cell lines were used for dynamic (90 min) and static(75 min p.i.) μPET imaging, as well as for biodistribution (90 min p.i.). Structure-activity-relationshipswere established by comparison with the predecessor compound Ga-68-TRAP(AvB6)3. Ga-68-Trivehexin was tested for in-human PET/CT imaging of HNSCC, parotideal adenocarcinoma, andPDAC.ResultsGa-68-Trivehexin showed a high αvβ6-integrin affinity (IC50 = 0.033 nM), selectivity over othersubtypes (IC50-based factors: αvβ8, 188; αvβ3, 82; α5β1, 667), blockable uptake in H2009 cells, andnegligible uptake in MDA-MB-231 cells. Biodistribution and preclinical PET imaging confirmed a hightarget-specific uptake in tumor and a low non-specific uptake in other organs and tissues except theexcretory organs (kidneys and urinary bladder). Preclinical PET corresponded well to in-human results,showing high and persistent uptake in metastatic PDAC and HNSCC (SUVmax = 10–13) as well as inkidneys/urine. Ga-68-Trivehexin enabled PET/CT imaging of small PDAC metastases and showed highuptake in HNSCC but not in tumor-associated inflammation.ConclusionsGa-68-Trivehexin is a valuable probe for imaging of αvβ6-integrin expression in human cancers.

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Section: Introductionmentioning

confidence: 99%

“…Multimerization is a venerable concept, and its theoretical foundations have been established decades ago [ 1 ]. There is no general doubt about the potential benefits of combining more than one targeting moiety (receptor ligands, enzyme inhibitors, antibodies or -fragments, or others), in view of a solid body of evidence that multimers invariantly exhibit a higher avidity than monomers [ 1 , 2 ]. Böhmer et al nevertheless pointed out that in despite of the long-known, huge potential of multimers and a lot of pertinent research, such compounds have made no impact in molecular imaging beyond the in vitro or preclinical levels [ 1 ], aside from full-size antibodies which are natural dimers of targeting proteins.…”

Section: Introductionmentioning

confidence: 99%

There is a world beyond αvβ3-integrin: Multimeric ligands for imaging of the integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1 by positron emission tomography

et al. 2021

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Background In the context of nuclear medicine and theranostics, integrin-related research and development was, for most of the time, focused predominantly on 'RGD peptides' and the subtype αvβ3-integrin. However, there are no less than 24 known integrins, and peptides without the RGD sequence as well as non-peptidic ligands play an equally important role as selective integrin ligands. On the other hand, multimerization is a well-established method to increase the avidity of binding structures, but multimeric radiopharmaceuticals have not made their way into clinics yet. In this review, we describe how these aspects have been interwoven in the framework of the German Research Foundation's multi-group interdisciplinary funding scheme CRC 824, yielding a series of potent PET imaging agents for selective imaging of various integrin subtypes. Results The gallium-68 chelator TRAP was utilized to elaborate symmetrical trimers of various peptidic and non-peptidic integrin ligands. Preclinical data suggested a high potential of the resulting Ga-68-tracers for PET-imaging of the integrins α5β1, αvβ8, αvβ6, and αvβ3. For the first three, we provide some additional immunohistochemistry data in human cancers, which suggest several future clinical applications. Finally, application of αvβ3- and αvβ6-integrin tracers in pancreatic carcinoma patients revealed that unlike αvβ3-targeted PET, αvβ6-integrin PET is not characterized by off-target uptake and thus, enables a substantially improved imaging of this type of cancer. Conclusions Novel radiopharmaceuticals targeting a number of different integrins, above all, αvβ6, have proven their clinical potential and will play an increasingly important role in future theranostics.

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Multivalent Probes in Molecular Imaging: Reality or Future?

Cited by 26 publications

References 99 publications

PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the “Cancer Integrin” αvβ6 with Ga-68-Trivehexin

PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the “Cancer Integrin” αvβ6 with Ga-68-Trivehexin

PET/CT Imaging of Head-and-Neck and Pancreatic Cancer in Humans by Targeting the "Cancer Integrin" αvβ6 with Ga-68-Trivehexin

There is a world beyond αvβ3-integrin: Multimeric ligands for imaging of the integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1 by positron emission tomography

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