The effect of macrocyclic chelators on the targeting properties of the 68 Ga-labeled gastrin releasing peptide receptor antagonist PEG 2 -RM26

Varasteh, Zohreh; Mitran, Bogdan; Rosenström, Ulrika; Velikyan, Irina; Rosestedt, Maria; Lindeberg, Gunnar; Sörensen, Jens; Larhed, Mats; Tolmachev, Vladimir; Orlova, Anna

doi:10.1016/j.nucmedbio.2014.12.009

Cited by 48 publications

(88 citation statements)

References 26 publications

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“…DOTAGA and NODAGA have four and three carboxyl groups, respectively, for coordination with 68 Ga after conjugation with the peptide, whereas HBED‐CC has two phenolate oxygens and two carboxylic acid groups. Thus, 68 Ga‐DOTAGA and 68 Ga‐HBED‐CC complexes are uni‐negative (−1 charge) whereas 68 Ga‐NODAGA is neutral (0 charge) . c(KCNGRC) peptide was synthesized manually using Fmoc strategy, and the disulfide bond between two cysteines was formed by on‐resin cyclization.…”

Section: Discussionmentioning

confidence: 99%

“…There are earlier reports of conjugation of NGR peptides with DOTA and NOTA chelators and radiolabeling with 68 Ga as well as using 64 Cu for PET imaging of CD13 receptor‐positive tumors . Size, coordination, and the basic structure of the chelator have a definite influence on the biological behavior of radiotracers . In this report, we chose to study and compare the effect of two macrocyclic chelators, DOTAGA and NODAGA and an acyclic chelator, HBED‐CC on in vivo behavior of NGR peptide.…”

Section: Introductionmentioning

confidence: 99%

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Comparative evaluation of ⁶⁸Ga‐labeled NODAGA, DOTAGA, and HBED‐CC‐conjugated cNGR peptide chelates as tumor‐targeted molecular imaging probes

et al. 2017

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The biological behavior of Ga-based radiopharmaceuticals can be significantly affected by the chelators' attributes (size, charge, lipophilicity). Thus, this study aimed at examining the influence of three different chelators, DOTAGA, NODAGA, and HBED-CC on the distribution pattern of Ga-labeled NGR peptides targeting CD13 receptors. Ga-DOTAGA-c(NGR), Ga-NODAGA-c(NGR), and Ga-HBED-CC-c(NGR) were observed to be hydrophilic with respective log p values being -3.5 ± 0.2, -3.3 ± 0.08, and -2.8 ± 0.14. The three radiotracers exhibited nearly similar uptake in human fibrosarcoma HT-1080 tumor cells with 86%, 63%, and 33% reduction during blocking studies with unlabeled cNGR peptide for Ga-DOTAGA-c(NGR), Ga-NODAGA-c(NGR), and Ga-HBED-CC-c(NGR), respectively, indicating higher receptor specificity of the first two radiotracers. The neutral radiotracer Ga-NODAGA-c(NGR) demonstrated better target-to-non-target ratios during in vivo studies compared to its negatively charged counterparts, Ga-DOTAGA-c(NGR) and Ga-HBED-CC-c(NGR). The three radiotracers had similar HT-1080 tumor uptake and being hydrophilic exhibited renal excretion with minimal uptake in non-target organs. Significant reduction (p< .005) in HT-1080 tumor uptake of the radiotracers was observed during blocking studies. It may be inferred from these studies that the three radiotracers are promising probes for in vivo imaging of CD13 receptor expressing cancer sites; however, Ga-NODAGA-c(NGR) is a better candidate.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparative evaluation of ⁶⁸Ga‐labeled NODAGA, DOTAGA, and HBED‐CC‐conjugated cNGR peptide chelates as tumor‐targeted molecular imaging probes

et al. 2017

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“…In the present work, we have modified the same GRPR‐antagonist RM26 by coupling tri‐ and tetra‐aza macrocyclic chelators to its N‐terminus via a PEG 2 ‐linker and investigated the respective 177 Lu‐labeled radiopeptides for their efficacy in GRPR‐targeted radiotherapy of prostate cancer in preclinical models. Previous studies have revealed a pronounced effect of the radiometal‐chelate on the biodistribution of RM26 in mice . Based on the newly acquired in vitro and in vivo data we have concluded that the tetra‐aza chelators DOTAGA and DOTA resulted in 177 Lu‐radioligands with the most suitable properties for TRT, showing a significantly higher tumor uptake compared to the NODAGA‐carrying radioligand.…”

Section: Discussionmentioning

confidence: 78%

“…The synthesis of X‐PEG 2 ‐RM26 (X = NOTA, NODAGA, DOTA, DOTAGA) by solid‐phase peptide synthesis (SPPS) was previously reported (Supporting Information Fig. S1).…”

Section: Methodsmentioning

confidence: 99%

“…The effects of the PEG spacer's length on overall hydrophilicity were found to be minor . However, the use of different macrocyclic chelators had a profound influence on the biodistribution profile of the radiolabeled conjugates . In this regard, both the geometry and the net charge of the radionuclide–chelator complex were identified as important factors influencing the blood clearance, activity uptake in tumors and normal organs, and kidney activity retention.…”

Section: Introductionmentioning

confidence: 99%

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Trastuzumab cotreatment improves survival of mice with PC‐3 prostate cancer xenografts treated with the GRPR antagonist ¹⁷⁷Lu‐DOTAGA‐PEG₂‐RM26

Mitran

Rinne

Konijnenberg

et al. 2019

Intl Journal of Cancer

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Gastrin‐releasing peptide receptors (GRPRs) are overexpressed in prostate cancer and are suitable for targeted radionuclide therapy (TRT). We optimized the bombesin‐derived GRPR‐antagonist PEG2‐RM26 for labeling with 177Lu and further determined the effect of treatment with 177Lu‐labeled peptide alone or in combination with the anti‐HER2 antibody trastuzumab in a murine model. The PEG2‐RM26 analog was coupled to NOTA, NODAGA, DOTA and DOTAGA chelators. The peptide‐chelator conjugates were labeled with 177Lu and characterized in vitro and in vivo. A preclinical therapeutic study was performed in PC‐3 xenografted mice. Mice were treated with intravenous injections (6 cycles) of (A) PBS, (B) DOTAGA‐PEG2‐RM26, (C) 177Lu‐DOTAGA‐PEG2‐RM26, (D) trastuzumab or (E) 177Lu‐DOTAGA‐PEG2‐RM26 in combination with trastuzumab. 177Lu‐DOTAGA‐PEG2‐RM26 demonstrated quantitative labeling yield at high molar activity (450 GBq/μmol), high in vivo stability (5 min pi >98% of radioligand remained when coinjected with phosphoramidon), high affinity to GRPR (K D = 0.4 ± 0.2 nM), and favorable biodistribution (1 hr pi tumor uptake was higher than in healthy tissues, including the kidneys). Therapy with 177Lu‐DOTAGA‐PEG2‐RM26 induced a significant inhibition of tumor growth. The median survival for control groups was significantly shorter than for treated groups (Group C 66 days, Group E 74 days). Trastuzumab together with radionuclide therapy significantly improved survival. No treatment‐related toxicity was observed. In conclusion, based on in vitro and in vivo characterization of the four 177Lu‐labeled PEG2‐RM26 analogs, we concluded that 177Lu‐DOTAGA‐PEG2‐RM26 was the most promising analog for TRT. Radiotherapy using 177Lu‐DOTAGA‐PEG2‐RM26 effectively inhibited tumor growth in vivo in a murine prostate cancer model. Anti‐HER2 therapy additionally improved survival.

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Synthesis of a Bifunctional Cross‐Bridged Chelating Agent, Peptide Conjugation, and Comparison of ⁶⁸Ga Labeling and Complex Stability Characteristics with Established Chelators

et al. 2022

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Ga 3 + can be introduced into receptor-specific peptidic carriers via different chelators to obtain radiotracers for Positron Emission Tomography imaging and the chosen chelating agent considerably influences the in vivo pharmacokinetics of the corresponding radiopeptides. A chelator that should be a valuable alternative to established chelating agents for 68 Garadiolabeling of peptides would be a backbone-functionalized variant of the chelator CB-DO2A. Here, the bifunctional crossbridged chelating agent CB-DO2A-GA was developed and compared to the established chelators DOTA, NODA-GA and DOTA-GA. For this purpose, CB-DO2A-GA(tBu) 2 was introduced into the peptide Tyr 3 -octreotate (TATE) and in direct comparison to the corresponding DOTA-, NODA-GA-, and DOTA-GA-modi-fied TATE analogs, CB-DO2A-GA-TATE required harsher reaction conditions for 68 Ga-incorporation. Regarding the hydrophilicity profile of the resulting radiopeptides, a decrease in hydrophilicity from [ 68 Ga]Ga-DOTA-GA-TATE (log D(7.4) of À 4.11 � 0.11) to [ 68 Ga]Ga-CB-DO2A-GA-TATE (À 3.02 � 0.08) was observed. Assessing the stability against metabolic degradation and complex challenge, [ 68 Ga]Ga-CB-DO2A-GA demonstrated a very high kinetic inertness, exceeding that of [ 68 Ga]Ga-DOTA-GA. Therefore, CB-DO2A-GA is a valuable alternative to established chelating agents for 68 Ga-radiolabeling of peptides, especially when the formation of a very stable, positively charged 68 Gacomplex is pursued.

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The effect of macrocyclic chelators on the targeting properties of the 68 Ga-labeled gastrin releasing peptide receptor antagonist PEG 2 -RM26

Cited by 48 publications

References 26 publications

Comparative evaluation of ⁶⁸Ga‐labeled NODAGA, DOTAGA, and HBED‐CC‐conjugated cNGR peptide chelates as tumor‐targeted molecular imaging probes

Comparative evaluation of ⁶⁸Ga‐labeled NODAGA, DOTAGA, and HBED‐CC‐conjugated cNGR peptide chelates as tumor‐targeted molecular imaging probes

Trastuzumab cotreatment improves survival of mice with PC‐3 prostate cancer xenografts treated with the GRPR antagonist ¹⁷⁷Lu‐DOTAGA‐PEG₂‐RM26

Synthesis of a Bifunctional Cross‐Bridged Chelating Agent, Peptide Conjugation, and Comparison of ⁶⁸Ga Labeling and Complex Stability Characteristics with Established Chelators

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The effect of macrocyclic chelators on the targeting properties of the 68 Ga-labeled gastrin releasing peptide receptor antagonist PEG 2 -RM26

Cited by 48 publications

References 26 publications

Comparative evaluation of 68Ga‐labeled NODAGA, DOTAGA, and HBED‐CC‐conjugated cNGR peptide chelates as tumor‐targeted molecular imaging probes

Comparative evaluation of 68Ga‐labeled NODAGA, DOTAGA, and HBED‐CC‐conjugated cNGR peptide chelates as tumor‐targeted molecular imaging probes

Trastuzumab cotreatment improves survival of mice with PC‐3 prostate cancer xenografts treated with the GRPR antagonist 177Lu‐DOTAGA‐PEG2‐RM26

Synthesis of a Bifunctional Cross‐Bridged Chelating Agent, Peptide Conjugation, and Comparison of 68Ga Labeling and Complex Stability Characteristics with Established Chelators

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Comparative evaluation of ⁶⁸Ga‐labeled NODAGA, DOTAGA, and HBED‐CC‐conjugated cNGR peptide chelates as tumor‐targeted molecular imaging probes

Comparative evaluation of ⁶⁸Ga‐labeled NODAGA, DOTAGA, and HBED‐CC‐conjugated cNGR peptide chelates as tumor‐targeted molecular imaging probes

Trastuzumab cotreatment improves survival of mice with PC‐3 prostate cancer xenografts treated with the GRPR antagonist ¹⁷⁷Lu‐DOTAGA‐PEG₂‐RM26

Synthesis of a Bifunctional Cross‐Bridged Chelating Agent, Peptide Conjugation, and Comparison of ⁶⁸Ga Labeling and Complex Stability Characteristics with Established Chelators