Glu-Ureido–Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers

Kopka, Klaus; Benešová, Martina; Bařinka, Cyril; Haberkorn, Uwe; Babich, John W.

doi:10.2967/jnumed.116.186775

Cited by 117 publications

(102 citation statements)

References 94 publications

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“…However, there exist some hints that such simultaneous bindings can occur thereby improving the binding affinity of the respective heterodimer, e.g., melanocortin-4 and CCK-2. 37,68 Apart from binding affinity, the successful application of monomeric PSMA radioligands was also associated with their internalization behavior, 12,20,69,70 and this was also true for GRPr agonists. 71,72 In the case of the [ 68 Ga] GaHBED-CC-heterodimer, 1, cell-internalization was not significantly different in comparison with the monomers.…”

Section: Discussion and Conclusion Remarksmentioning

confidence: 98%

“…Salivary glands uptake is considered a major side effect of theranostic PSMA ligands at the moment. 20,66 Moreover, the replacement of the GRPr side with an antagonist could also be beneficial for heterodimers since radiolabeled GRP receptor antagonists are known to have high tumor uptake, resulting in high tumor-to-kidney ratios and slow tumor washout. In addition GRPr antagonists have shown reduced physiologic activity and offtarget radioactivity accumulation, suggesting improved in vivo performance compared with bombesin agonists.…”

Section: In Vivo Evaluation In Micementioning

confidence: 99%

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Bispecific radioligands targeting prostate‐specific membrane antigen and gastrin‐releasing peptide receptors on the surface of prostate cancer cells

Liolios

Sachpekidis

Schäfer

et al. 2019

Labelled Comp Radiopharmac

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Metastases of prostate cancer usually show highly heterogeneous or partly lost prostate-specific membrane antigen (PSMA) expression. In order to image and treat both PSMA positive and negative tissues, the extension of PSMA tracer specificity to other receptors, also highly expressed on the surface of prostate cancer cells, has been suggested. Prostate cancer cells usually express both PSMA and gastrin-releasing peptide (GRP) receptors; thus, bispecific heterodimeric molecules, addressing both targets at the same time, may significantly improve prostate cancer imaging and therapy. This article summarizes preclinical data regarding low-molecular weight molecules targeting PSMA and GRP receptors.

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Section: Discussion and Conclusion Remarksmentioning

confidence: 98%

Section: In Vivo Evaluation In Micementioning

confidence: 99%

Bispecific radioligands targeting prostate‐specific membrane antigen and gastrin‐releasing peptide receptors on the surface of prostate cancer cells

Liolios

Sachpekidis

Schäfer

et al. 2019

Labelled Comp Radiopharmac

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“…It has been reported that the glutamate moiety on urea-based PSMA inhibitors interacts with the S1 binding pocket, which can interact with lipophilic spacers. The S1 binding pocket is a funnel-shaped tunnel with a depth of approximately 20 Å and a width of 8−9 Å [48][49][50]. The synergistic effect of a glutamate motif and a lipophilic spacer determines the internalization potency of PSMA inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Evaluation of 99mTc-Tricabonyl Labeled Isonitrile Conjugates for Prostate-Specific Membrane Antigen (PSMA) Image

et al. 2020

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Prostate-specific membrane antigen (PSMA) is a biomarker expressed on the surface of prostate cancer (PCa). In an effort to improve the detection and treatment of PCa, small urea-based PSMA inhibitors have been studied extensively. In the present study, we aimed to develop 99mTc-tricabonyl labeled urea-based PSMA conjugates containing isonitrile (CN-R)-coordinating ligands ([99mTc]Tc-15 and [99mTc]Tc-16). Both the PSMA conjugates were obtained at high radiochemical efficiency (≥98.5%). High in vitro binding affinity was observed for [99mTc]Tc-15 and [99mTc]Tc-16 (Kd = 5.5 and 0.2 nM, respectively) in PSMA-expressing 22Rv1 cells. Tumor xenografts were conducted using 22Rv1 cells and rapid accumulation of [99mTc]Tc-16 (1.87 ± 0.11% ID/g) was observed at 1 h post-injection, which subsequently increased to (2.83 ± 0.26% ID/g) at 4 h post-injection. However, [99mTc]Tc-15 showed moderate tumor uptake (1.48 ± 0.18% ID/g), which decreased at 4 h post-injection (0.81 ± 0.09% ID/g). [99mTc]Tc-16 was excreted from non-targeted tissues with high tumor-to-blood (17:1) and tumor-to-muscle ratio (41:1) at 4 h post-injection at approximately 4 times higher levels than [99mTc]Tc-15. Uptakes of [99mTc]Tc-15 and [99mTc]Tc-16 to PSMA-expressing tumor and tissues were significantly blocked by co-injection of 2-(Phosphonomethyl)-pentandioic acid (2-PMPA), suggesting that their uptakes are mediated by PSMA specifically. Whole-body single photon emission computed tomography imaging of [99mTc]Tc-16 verified the ex vivo biodistribution results and demonstrated clear visualization of tumors and tissues expressing PSMA compared to [99mTc]Tc-15. In conclusion, using [99mTc]Tc-16 rather than [99mTc]Tc-15 may be the preferable because of its relatively high tumor uptake and retention.

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“…PSMA radiotherapy is a promising treatment for mCRPC with multiple radionuclideconjugated small molecule PSMA ligands in clinical development (6,7,36). 177 Lu-PSMA-617 has shown efficacy in hundreds of mCRPC patients, but high specific uptake into salivary glands and kidneys has resulted in xerostomia and potential for nephrotoxicity (5,8).…”

Section: Discussionmentioning

confidence: 99%

JHU-2545 Selectively Shields Salivary Glands and Kidneys during PSMA-Targeted Radiotherapy

Nedelcovych

Dash

et al. 2018

Preprint

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PURPOSEProstate-specific membrane antigen (PSMA) radiotherapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC) with several beta or alpha particle-emitting radionuclide-conjugated small molecules showing efficacy in late stage patients. However, PSMA is also expressed in kidneys and salivary glands where specific uptake causes dose-limiting xerostomia and potential for nephrotoxicity. The PSMA inhibitor 2- (phosphonomethyl)pentanedioic acid (2-PMPA) can prevent kidney uptake in mice, but also blocks tumor uptake, precluding its clinical utility. Selective delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radiotherapy.EXPERIMENTAL DESIGNA tri-alkoxycarbonyloxy alkyl (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Preclinical pharmacokinetic and imaging experiments were conducted prior to assessment in 3 mCRPC patients receiving PSMA PET and radiotherapy.RESULTSJHU-2545 resulted in 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 h*nmol/g) and kidneys (359 ± 4.16 h*nmol/g) versus prostate tumor xenograft (6.79 ± 0.19 h*nmol/g). JHU-2545 also blocked rodent kidneys and salivary glands uptake of the PSMA PET tracers 68Ga-PSMA-11 and 18F-DCFPyL by up to 85% without effect on tumor. In a mCRPC patient, JHU-2545 treatment prior to 68Ga-PSMA-617 administration reduced kidney SUVmax by 76% without effect on metastatic lesions. When administered prior to injection of the beta emitter 177Lu-PSMA-617, JHU-2545 shielded both the salivary glands (72% Gy reduction) and kidneys (45% Gy reduction) without effect on metastases’ dose.CONCLUSIONSJHU-2545 pre-treatment raises the cumulative dose limit and improves the safety and efficacy profile of PSMA radiotherapy.STATEMENT OF TRANSLATIONAL RELEVANCEProstate Specific Membrane Antigen (PSMA) molecular radiotherapy has emerged as a promising treatment for metastatic castration-resistant prostate cancer (mCRPC), but endogenous expression of PSMA in kidneys and salivary glands causes uptake into these organs resulting in dose-limiting toxicities. We describe the discovery of JHU-2545, a PSMA inhibitor prodrug that selectively blocks kidney and salivary gland uptake of PSMA theranostics without altering tumor uptake in both preclinical models and in mCRPC patients. Pretreatment of JHU-2545 thereby improves the safety and efficacy profile of the multiple PSMA radiotherapies in development.

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Glu-Ureido–Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers

Cited by 117 publications

References 94 publications

Bispecific radioligands targeting prostate‐specific membrane antigen and gastrin‐releasing peptide receptors on the surface of prostate cancer cells

Bispecific radioligands targeting prostate‐specific membrane antigen and gastrin‐releasing peptide receptors on the surface of prostate cancer cells

Synthesis and Evaluation of 99mTc-Tricabonyl Labeled Isonitrile Conjugates for Prostate-Specific Membrane Antigen (PSMA) Image

JHU-2545 Selectively Shields Salivary Glands and Kidneys during PSMA-Targeted Radiotherapy

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