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Keywords = minigastrin

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14 pages, 1877 KiB  
Article
Development of the First 18F-Labeled Radiohybrid-Based Minigastrin Derivative with High Target Affinity and Tumor Accumulation by Substitution of the Chelating Moiety
by Thomas Günther, Nadine Holzleitner, Daniel Di Carlo, Nicole Urtz-Urban, Constantin Lapa and Hans-Jürgen Wester
Pharmaceutics 2023, 15(3), 826; https://doi.org/10.3390/pharmaceutics15030826 - 3 Mar 2023
Cited by 6 | Viewed by 2507
Abstract
In order to optimize elevated kidney retention of previously reported minigastrin derivatives, we substituted (R)-DOTAGA by DOTA in (R)-DOTAGA-rhCCK-16/-18. CCK-2R-mediated internalization and affinity of the new compounds were determined using AR42J cells. Biodistribution and µSPECT/CT imaging studies at [...] Read more.
In order to optimize elevated kidney retention of previously reported minigastrin derivatives, we substituted (R)-DOTAGA by DOTA in (R)-DOTAGA-rhCCK-16/-18. CCK-2R-mediated internalization and affinity of the new compounds were determined using AR42J cells. Biodistribution and µSPECT/CT imaging studies at 1 and 24 h p.i. were carried out in AR42J tumor-bearing CB17-SCID mice. Both DOTA-containing minigastrin analogs exhibited 3- to 5-fold better IC50 values than their (R)-DOTAGA-counterparts. natLu-labeled peptides revealed higher CCK-2R affinity than their natGa-labeled analogs. In vivo, tumor uptake at 24 h p.i. of the most affine compound, [19F]F-[177Lu]Lu-DOTA-rhCCK-18, was 1.5- and 13-fold higher compared to its (R)-DOTAGA derivative and the reference compound, [177Lu]Lu-DOTA-PP-F11N, respectively. However, activity levels in the kidneys were elevated as well. At 1 h p.i., tumor and kidney accumulation of [19F]F-[177Lu]Lu-DOTA-rhCCK-18 and [18F]F-[natLu]Lu-DOTA-rhCCK-18 was high. We could demonstrate that the choice of chelators and radiometals has a significant impact on CCK-2R affinity and thus tumor uptake of minigastrin analogs. While elevated kidney retention of [19F]F-[177Lu]Lu-DOTA-rhCCK-18 has to be further addressed with regard to radioligand therapy, its radiohybrid analog, [18F]F-[natLu]Lu-DOTA-rhCCK-18, might be ideal for positron emission tomography (PET) imaging due to its high tumor accumulation at 1 h p.i. and the attractive physical properties of fluorine-18. Full article
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16 pages, 1913 KiB  
Article
Effect of N-Terminal Peptide Modifications on In Vitro and In Vivo Properties of 177Lu-Labeled Peptide Analogs Targeting CCK2R
by Anton Amadeus Hörmann, Maximilian Klingler, Christine Rangger, Christian Mair, Lieke Joosten, Gerben M. Franssen, Peter Laverman and Elisabeth von Guggenberg
Pharmaceutics 2023, 15(3), 796; https://doi.org/10.3390/pharmaceutics15030796 - 28 Feb 2023
Cited by 6 | Viewed by 2286
Abstract
The therapeutic potential of minigastrin (MG) analogs for the treatment of cholecystokinin-2 receptor (CCK2R)-expressing cancers is limited by poor in vivo stability or unfavorable accumulation in non-target tissues. Increased stability against metabolic degradation was achieved by modifying the C-terminal receptor-specific region. This modification [...] Read more.
The therapeutic potential of minigastrin (MG) analogs for the treatment of cholecystokinin-2 receptor (CCK2R)-expressing cancers is limited by poor in vivo stability or unfavorable accumulation in non-target tissues. Increased stability against metabolic degradation was achieved by modifying the C-terminal receptor-specific region. This modification led to significantly improved tumor targeting properties. In this study, further N-terminal peptide modifications were investigated. Two novel MG analogs were designed starting from the amino acid sequence of DOTA-MGS5 (DOTA-DGlu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH2). Introduction of a penta-DGlu moiety and replacement of the four N-terminal amino acids by a non-charged hydrophilic linker was investigated. Retained receptor binding was confirmed using two CCK2R-expressing cell lines. The effect on metabolic degradation of the new 177Lu-labeled peptides was studied in human serum in vitro, as well as in BALB/c mice in vivo. The tumor targeting properties of the radiolabeled peptides were assessed using BALB/c nude mice bearing receptor-positive and receptor-negative tumor xenografts. Both novel MG analogs were found to have strong receptor binding, enhanced stability, and high tumor uptake. Replacement of the four N-terminal amino acids by a non-charged hydrophilic linker lowered the absorption in the dose-limiting organs, whereas introduction of the penta-DGlu moiety increased uptake in renal tissue. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Cancer Imaging and Therapy)
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17 pages, 1263 KiB  
Article
Effects of Side Chain and Peptide Bond Modifications on the Targeting Properties of Stabilized Minigastrin Analogs
by Taraneh Sadat Zavvar, Anton Amadeus Hörmann, Maximilian Klingler, Dominik Summer, Christine Rangger, Laurence Desrues, Hélène Castel, Pierrick Gandolfo and Elisabeth von Guggenberg
Pharmaceuticals 2023, 16(2), 278; https://doi.org/10.3390/ph16020278 - 13 Feb 2023
Cited by 4 | Viewed by 3107
Abstract
Different attempts have been made in the past two decades to develop radiolabeled peptide conjugates with enhanced pharmacokinetic properties in order to improve the application for tumor imaging and peptide receptor radionuclide therapy (PRRT), which targets the cholecystokinin-2 receptor (CCK2R). In this paper, [...] Read more.
Different attempts have been made in the past two decades to develop radiolabeled peptide conjugates with enhanced pharmacokinetic properties in order to improve the application for tumor imaging and peptide receptor radionuclide therapy (PRRT), which targets the cholecystokinin-2 receptor (CCK2R). In this paper, the influence of different side chain and peptide bond modifications has been explored for the minigastrin analog DOTA-DGlu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH2 (DOTA-MGS5). Based on this lead structure, five new derivatives were synthesized for radiolabeling with trivalent radiometals. Different chemical and biological properties of the new derivatives were analyzed. Receptor interaction of the peptide derivatives and cell internalization of the radiolabeled peptides were studied in A431-CCK2R cells. The stability of the radiolabeled peptides in vivo was investigated using BALB/c mice. Tumor targeting of all 111In-labeled peptide conjugates, and of a selected compound radiolabeled with gallium-68 and lutetium-177, was evaluated in BALB/c nude mice xenografted with A431-CCK2R and A431-mock cells. All 111In-labeled conjugates, except [111In]In-DOTA-[Phe8]MGS5, showed a high resistance against enzymatic degradation. A high receptor affinity with IC50 values in the low nanomolar range was confirmed for most of the peptide derivatives. The specific cell internalization over time was 35.3–47.3% for all radiopeptides 4 h after incubation. Only [111In]In-DOTA-MGS5[NHCH3] exhibited a lower cell internalization of 6.6 ± 2.8%. An overall improved resistance against enzymatic degradation was confirmed in vivo. Of the radiopeptides studied, [111In]In-DOTA-[(N-Me)1Nal8]MGS5 showed the most promising targeting properties, with significantly increased accumulation of radioactivity in A431-CCK2R xenografts (48.1 ± 9.2% IA/g) and reduced accumulation of radioactivity in stomach (4.2 ± 0.5% IA/g). However, in comparison with DOTA-MGS5, a higher influence on the targeting properties was observed for the change of radiometal, resulting in a tumor uptake of 15.67 ± 2.21% IA/g for [68Ga]Ga-DOTA-[(N-Me)1Nal8]MGS5 and 35.13 ± 6.32% IA/g for [177Lu]Lu-DOTA-[(N-Me)1Nal8]MGS5. Full article
(This article belongs to the Special Issue Tumor-Targeting Radioligands for Molecular Imaging and Therapy)
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12 pages, 2112 KiB  
Article
Introduction of a SiFA Moiety into the D-Glutamate Chain of DOTA-PP-F11N Results in Radiohybrid-Based CCK-2R-Targeted Compounds with Improved Pharmacokinetics In Vivo
by Nadine Holzleitner, Thomas Günther, Roswitha Beck, Constantin Lapa and Hans-Jürgen Wester
Pharmaceuticals 2022, 15(12), 1467; https://doi.org/10.3390/ph15121467 - 25 Nov 2022
Cited by 10 | Viewed by 2816
Abstract
In order to enable 18F- and 177Lu-labelling within the same molecule, we introduced a silicon-based fluoride acceptor (SiFA) into the hexa-D-glutamate chain of DOTA-PP-F11N. In addition, minigastrin analogues with a prolonged as well as γ-linked D-glutamate chain were synthesised and [...] Read more.
In order to enable 18F- and 177Lu-labelling within the same molecule, we introduced a silicon-based fluoride acceptor (SiFA) into the hexa-D-glutamate chain of DOTA-PP-F11N. In addition, minigastrin analogues with a prolonged as well as γ-linked D-glutamate chain were synthesised and evaluated. CCK-2R affinity (IC50, AR42J cells) and lipophilicity (logD7.4) were determined. Biodistribution studies at 24 h post-injection (p.i.) and µSPECT/CT imaging at 1, 4 and 24 h p.i. were carried out in AR42J tumour-bearing CB17-SCID mice. CCK-2R affinity of (R)-DOTAGA-rhCCK-1 to 18 was enhanced with increasing distance between the SiFA building block and the binding motif. Lipophilicity of [177Lu]Lu-(R)-DOTAGA-rhCCK-1 to 18 was higher compared to that of [177Lu]Lu-DOTA-PP-F11N and [177Lu]Lu-CP04. The respective α- and γ-linked rhCCK derivatives revealing the highest CCK-2R affinity were further evaluated in vivo. In comparison with [177Lu]Lu-DOTA-PP-F11N, [177Lu-]Lu-(R)-DOTAGA-rhCCK-9 and -16 exhibited three- to eight-fold increased activity levels in the tumour at 24 h p.i. However, activity levels in the kidneys were elevated as well. We could show that the introduction of a lipophilic SiFA moiety into the hydrophilic backbone of [177Lu]Lu-DOTA-PP-F11N led to a decelerated blood clearance and thus improved tumour retention. However, elevated kidney retention has to be addressed in future studies. Full article
(This article belongs to the Special Issue Tumor-Targeting Radioligands for Molecular Imaging and Therapy)
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14 pages, 1611 KiB  
Article
Automated Synthesis of 68Ga-Labeled DOTA-MGS8 and Preclinical Characterization of Cholecystokinin-2 Receptor Targeting
by Anton Amadeus Hörmann, Elisabeth Plhak, Maximilian Klingler, Christine Rangger, Joachim Pfister, Gert Schwach, Herbert Kvaternik and Elisabeth von Guggenberg
Molecules 2022, 27(6), 2034; https://doi.org/10.3390/molecules27062034 - 21 Mar 2022
Cited by 8 | Viewed by 3592
Abstract
The new minigastrin analog DOTA-MGS8 targeting the cholecystokinin-2 receptor (CCK2R) used in this study displays the combination of two site-specific modifications within the C-terminal receptor binding sequence together with an additional N-terminal amino acid substitution preventing fast metabolic degradation. Within this study, the [...] Read more.
The new minigastrin analog DOTA-MGS8 targeting the cholecystokinin-2 receptor (CCK2R) used in this study displays the combination of two site-specific modifications within the C-terminal receptor binding sequence together with an additional N-terminal amino acid substitution preventing fast metabolic degradation. Within this study, the preparation of 68Ga-labeled DOTA-MGS8 was validated using an automated synthesis module, describing the specifications and analytical methods for quality control for possible clinical use. In addition, preclinical studies were carried out to characterize the targeting potential. [68Ga]Ga-DOTA-MGS8 showed a high receptor-specific cell internalization into AR42J rat pancreatic cells (~40%) with physiological expression of rat CCK2R as well as A431-CCK2R cells transfected to stably express human CCK2R (~47%). A favorable biodistribution profile was observed in BALB/c nude mice xenografted with A431-CCK2R cells and mock-transfected A431 cells as control. The high tumor uptake of ~27% IA/g together with low background activity and limited uptake in non-target tissue confirms the potential for high-sensitivity positron emission tomography of stabilized MG analogs in patients with MTC and other CCK2R-related malignancies. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging 2021)
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8 pages, 1698 KiB  
Article
Therapeutic Response of CCKBR-Positive Tumors to Combinatory Treatment with Everolimus and the Radiolabeled Minigastrin Analogue [177Lu]Lu-PP-F11N
by Michal Grzmil, Stefan Imobersteg, Alain Blanc, Stephan Frank, Roger Schibli and Martin P. Béhé
Pharmaceutics 2021, 13(12), 2156; https://doi.org/10.3390/pharmaceutics13122156 - 15 Dec 2021
Cited by 6 | Viewed by 3967
Abstract
The inhibition of the mammalian target of rapamycin complex 1 (mTORC1) by everolimus (RAD001) was recently shown to enhance the tumor uptake of radiolabeled minigastrin. In this paper, we investigate if this finding can improve the in vivo therapeutic response to [177 [...] Read more.
The inhibition of the mammalian target of rapamycin complex 1 (mTORC1) by everolimus (RAD001) was recently shown to enhance the tumor uptake of radiolabeled minigastrin. In this paper, we investigate if this finding can improve the in vivo therapeutic response to [177Lu]Lu-PP-F11N treatment. The N-terminal DOTA-conjugated gastrin analogue PP-F11N (DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe) was used to evaluate treatment efficacy in the human A431/CCKBR xenograft nude mouse model in combination with RAD001. Both RAD001 and [177Lu]Lu-PP-F11N single treatments as well as their combination inhibited tumor growth and increased survival. In concomitantly treated mice, the average tumor size and median survival time were significantly reduced and extended, respectively, as compared to the monotherapies. The histological analysis of kidney and stomach dissected after treatment with RAD001 and [177Lu]Lu-PP-F11N did not indicate significant adverse effects. In conclusion, our study data demonstrate the potential of mTORC1 inhibition to substantially improve the therapeutic efficacy of radiolabeled minigastrin analogues in CCKBR-positive cancers. Full article
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17 pages, 4668 KiB  
Review
Update on Preclinical Development and Clinical Translation of Cholecystokinin-2 Receptor Targeting Radiopharmaceuticals
by Elisabeth von Guggenberg, Petra Kolenc, Christof Rottenburger, Renata Mikołajczak and Alicja Hubalewska-Dydejczyk
Cancers 2021, 13(22), 5776; https://doi.org/10.3390/cancers13225776 - 18 Nov 2021
Cited by 22 | Viewed by 4451
Abstract
The cholecystokinin-2 receptor (CCK2R) has been a target of interest for molecular imaging and targeted radionuclide therapy for two decades. However, so far CCK2R targeted imaging and therapy has not been introduced in clinical practice. Within this review the recent radiopharmaceutical development of [...] Read more.
The cholecystokinin-2 receptor (CCK2R) has been a target of interest for molecular imaging and targeted radionuclide therapy for two decades. However, so far CCK2R targeted imaging and therapy has not been introduced in clinical practice. Within this review the recent radiopharmaceutical development of CCK2R targeting compounds and the ongoing clinical trials are presented. Currently, new gastrin derivatives as well as nonpeptidic substances are being developed to improve the properties for clinical use. A team of specialists from the field of radiopharmacy and nuclear medicine reviewed the available literature and summarized their own experiences in the development and clinical testing of CCK2R targeting radiopharmaceuticals. The recent clinical trials with novel radiolabeled minigastrin analogs demonstrate the potential for both applications, imaging as well as targeted radiotherapy, and reinforce the clinical applicability within a theranostic concept. The intense efforts in optimizing CCK2R targeting radiopharmaceuticals has led to new substances for clinical use, as shown in first imaging studies in patients with advanced medullary thyroid cancer. The first clinical results suggest that the wider clinical implication of CCK2R-targeted radiopharmaceuticals is reasonable. Full article
(This article belongs to the Special Issue Radiopharmaceuticals for Oncological Diseases)
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17 pages, 1718 KiB  
Article
Radiopharmaceutical Formulation and Preclinical Testing of 68Ga-Labeled DOTA-MGS5 for the Regulatory Approval of a First Exploratory Clinical Trial
by Anton A. Hörmann, Maximilian Klingler, Christine Rangger, Christian Mair, Clemens Decristoforo, Christian Uprimny, Irene J. Virgolini and Elisabeth von Guggenberg
Pharmaceuticals 2021, 14(6), 575; https://doi.org/10.3390/ph14060575 - 16 Jun 2021
Cited by 12 | Viewed by 4178
Abstract
The new minigastrin analog DOTA-MGS5 is a promising new candidate for targeting cholecystokinin-2 receptor (CCK2R)-expressing tumors. To enable the clinical translation of PET/CT imaging using 68Ga-labeled DOTA-MGS5, different quality and safety aspects need to be considered to comply with the regulatory framework [...] Read more.
The new minigastrin analog DOTA-MGS5 is a promising new candidate for targeting cholecystokinin-2 receptor (CCK2R)-expressing tumors. To enable the clinical translation of PET/CT imaging using 68Ga-labeled DOTA-MGS5, different quality and safety aspects need to be considered to comply with the regulatory framework for clinical trial application. The preparation of the radiopharmaceutical was established using a cassette-based automated synthesis unit. Product specifications, including analytical procedures and acceptance criteria, were adopted from Ph. Eur. monographs for other 68Ga-labeled radiopharmaceuticals. Non-clinical studies included receptor affinity and cell uptake studies using two different CCK2R-expressing cell lines, as well as pharmacokinetic biodistribution studies in BALB/c mice for dosimetry calculations and toxicological studies in Wistar rats. The produced masterbatches fulfilled the defined acceptance criteria. DOTA-MGS5, with confirmed affinity to the CCK2R, showed a high specific cell uptake and no interaction with other receptors in vitro when radiolabeled with gallium-68. Favorable in vivo properties were observed in biodistribution and dosimetry studies. An effective dose of ~0.01 mSv/MBq was estimated for humans utilizing OLINDA/EXM software. A maximum peptide dose of 50 µg was established for the initial clinical dose based on the toxicity study in rats. The standardized production of [68Ga]Ga-DOTA-MGS5 using an automated synthesis module and the performed non-clinical safety studies support a first exploratory clinical trial with this new PET imaging agent. Full article
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12 pages, 2985 KiB  
Article
Improved Tumor-Targeting with Peptidomimetic Analogs of Minigastrin 177Lu-PP-F11N
by Nathalie M. Grob, Roger Schibli, Martin Béhé and Thomas L. Mindt
Cancers 2021, 13(11), 2629; https://doi.org/10.3390/cancers13112629 - 27 May 2021
Cited by 11 | Viewed by 4209
Abstract
The cholecystokinin-2 receptor (CCK2R) is an attractive target in nuclear medicine due to its overexpression by different tumors. Several radiolabeled peptidic ligands targeting the CCK2R have been investigated in the past; however, their low stability against proteases can limit their uptake in tumors [...] Read more.
The cholecystokinin-2 receptor (CCK2R) is an attractive target in nuclear medicine due to its overexpression by different tumors. Several radiolabeled peptidic ligands targeting the CCK2R have been investigated in the past; however, their low stability against proteases can limit their uptake in tumors and metastases. Substitution of single or multiple amide bonds with metabolically stable 1,4-disubstituted 1,2,3-triazoles as amide bond bioisosteres proved a promising strategy for improving the tumor-targeting properties of a truncated analog of minigastrin. In this study, we applied the previously studied structural modifications to improve the pharmacokinetic and pharmacodynamic properties of PP-F11N, a minigastrin analog currently in clinical trials. Novel minigastrins (NMGs) as analogs of PP-F11N with one or two amide bonds substituted by 1,2,3-triazoles were synthesized, radiolabeled with 177Lu3+, and subjected to full evaluation in vitro (cell internalization, receptor affinity, stability in blood plasma) and in vivo (stability, biodistribution, SPECT/CT imaging). NMGs with triazoles inserted between the amino acids DGlu10-Ala11 and/or Tyr12-Gly13 showed a significantly increased cellular uptake and affinity toward the CCK2R in vitro. Resistance against the metabolic degradation of the NMGs was comparable to those of the clinical candidate PP-F11N. Imaging by SPECT/CT and biodistribution studies demonstrated a higher uptake in CCK2R-positive tumors but also in the CCK2R-positive stomach. The peptidomimetic compounds showed a slow tumor washout and high tumor-to-kidney ratios. The structural modifications led to the identification of analogs with promising properties for progression to clinical applications in the diagnosis and therapy of CCK2R-positive neoplasms. Full article
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12 pages, 2747 KiB  
Article
Evaluation of Actinium-225 Labeled Minigastrin Analogue [225Ac]Ac-DOTA-PP-F11N for Targeted Alpha Particle Therapy
by Yun Qin, Stefan Imobersteg, Alain Blanc, Stephan Frank, Roger Schibli, Martin P. Béhé and Michal Grzmil
Pharmaceutics 2020, 12(11), 1088; https://doi.org/10.3390/pharmaceutics12111088 - 12 Nov 2020
Cited by 23 | Viewed by 4410
Abstract
The overexpression of cholecystokinin B receptor (CCKBR) in human cancers led to the development of radiolabeled minigastrin analogues for targeted radionuclide therapy, which aims to deliver cytotoxic radiation specifically to cancer cells. Alpha emitters (e.g., actinium-225) possess high potency in cancer cell-killing and [...] Read more.
The overexpression of cholecystokinin B receptor (CCKBR) in human cancers led to the development of radiolabeled minigastrin analogues for targeted radionuclide therapy, which aims to deliver cytotoxic radiation specifically to cancer cells. Alpha emitters (e.g., actinium-225) possess high potency in cancer cell-killing and hold promise for the treatment of malignant tumors. In these preclinical studies, we developed and evaluated CCKBR-targeted alpha particle therapy. The cellular uptake and cytotoxic effect of actinium-225 labeled and HPLC-purified minigastrin analogue [225Ac]Ac-PP-F11N were characterized in the human squamous cancer A431 cells transfected with CCKBR. Nude mice bearing A431/CCKBR tumors were used for biodistribution and therapy studies followed by histological analysis and SPECT/CT imaging. In vitro, [225Ac]Ac-PP-F11N showed CCKBR-specific and efficient internalization rate and potent cytotoxicity. The biodistribution studies of [225Ac]Ac-PP-F11N revealed CCKBR-specific uptake in tumors, whereas the therapeutic studies demonstrated dose-dependent inhibition of tumor growth and extended mean survival time, without apparent toxicity. The histological analysis of kidney and stomach indicated no severe adverse effects after [225Ac]Ac-PP-F11N administration. The post-therapy SPECT-CT images with [111In]In-PP-F11N confirmed no CCKBR-positive tumor left in the mice with complete remission. In conclusion, our study demonstrates therapeutic efficacy of [225Ac]Ac-PP-F11N without acute radiotoxicity in CCKBR-positive cancer model. Full article
(This article belongs to the Special Issue Targeted Radionuclide Therapy)
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19 pages, 1961 KiB  
Article
Initial In Vitro and In Vivo Evaluation of a Novel CCK2R Targeting Peptide Analog Labeled with Lutetium-177
by Anton Amadeus Hörmann, Maximilian Klingler, Maliheh Rezaeianpour, Nikolas Hörmann, Ronald Gust, Soraya Shahhosseini and Elisabeth von Guggenberg
Molecules 2020, 25(19), 4585; https://doi.org/10.3390/molecules25194585 - 8 Oct 2020
Cited by 14 | Viewed by 3653
Abstract
Targeting of cholecystokinin-2 receptor (CCK2R) expressing tumors using radiolabeled minigastrin (MG) analogs is hampered by rapid digestion of the linear peptide in vivo. In this study, a new MG analog stabilized against enzymatic degradation was investigated in preclinical studies to characterize the metabolites [...] Read more.
Targeting of cholecystokinin-2 receptor (CCK2R) expressing tumors using radiolabeled minigastrin (MG) analogs is hampered by rapid digestion of the linear peptide in vivo. In this study, a new MG analog stabilized against enzymatic degradation was investigated in preclinical studies to characterize the metabolites formed in vivo. The new MG analog DOTA-DGlu-Pro-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH2 comprising site-specific amino acid substitutions in position 2, 6 and 8 and different possible metabolites thereof were synthesized. The receptor interaction of the peptide and selected metabolites was evaluated in a CCK2R-expressing cell line. The enzymatic stability of the 177Lu-labeled peptide analog was evaluated in vitro in different media as well as in BALB/c mice up to 1 h after injection and the metabolites were identified based on radio-HPLC analysis. The new radiopeptide showed a highly increased stability in vivo with >56% intact radiopeptide in the blood of BALB/c mice 1 h after injection. High CCK2R affinity and cell uptake was confirmed only for the intact peptide, whereas enzymatic cleavage within the receptor specific C-terminal amino acid sequence resulted in complete loss of affinity and cell uptake. A favorable biodistribution profile was observed in BALB/c mice with low background activity, preferential renal excretion and prolonged uptake in CCK2R-expressing tissues. The novel stabilized MG analog shows high potential for diagnostic and therapeutic use. The radiometabolites characterized give new insights into the enzymatic degradation in vivo. Full article
(This article belongs to the Special Issue Radiolabeled Compounds for Diagnosis and Treatment of Cancer)
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1 pages, 547 KiB  
Correction
Correction: Klingler, M., et al. Cholecystokinin-2 Receptor Targeting with Novel C-terminally Stabilized HYNIC-Minigastrin Analogs Radiolabeled with Technetium-99m. Pharmaceuticals 2019, 12, 13
by Maximilian Klingler, Christine Rangger, Dominik Summer, Piriya Kaeopookum, Clemens Decristoforo and Elisabeth von Guggenberg
Pharmaceuticals 2019, 12(2), 88; https://doi.org/10.3390/ph12020088 - 13 Jun 2019
Cited by 4 | Viewed by 3029
Abstract
In our paper [...] Full article
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15 pages, 2023 KiB  
Article
Cholecystokinin-2 Receptor Targeting with Novel C-terminally Stabilized HYNIC-Minigastrin Analogs Radiolabeled with Technetium-99m
by Maximilian Klingler, Christine Rangger, Dominik Summer, Piriya Kaeopookum, Clemens Decristoforo and Elisabeth von Guggenberg
Pharmaceuticals 2019, 12(1), 13; https://doi.org/10.3390/ph12010013 - 15 Jan 2019
Cited by 14 | Viewed by 4485 | Correction
Abstract
The high overexpression of cholecystokinin-2 receptors (CCK2R) in tumors, such as medullary thyroid carcinoma, allows for highly specific diagnostic and therapeutic targeting with radiolabeled peptide probes derived from natural ligands for the receptor. Based on the ideal imaging characteristics, high availability and low [...] Read more.
The high overexpression of cholecystokinin-2 receptors (CCK2R) in tumors, such as medullary thyroid carcinoma, allows for highly specific diagnostic and therapeutic targeting with radiolabeled peptide probes derived from natural ligands for the receptor. Based on the ideal imaging characteristics, high availability and low cost of technetium-99m (99mTc)-labeled radiopharmaceuticals we have developed two hydrazinonicotinic acid (HYNIC) conjugated minigastrin analogs allowing labeling at high specific activity. The CCK2R targeting peptide conjugates show specific amino acid substitutions in the C-terminal receptor-specific sequence with the aim to increase stability and tumor targeting. The CCK2R affinity and the cell uptake of the new radioligands were analyzed using A431 human epidermoid carcinoma cells stably transfected with human CCK2R and mock transfected cells. Metabolic studies in BALB/c mice revealed a high resistance against enzymatic degradation for both radioligands. Biodistribution studies in tumor-xenografted athymic BALB/c nude mice at 1 h and 4 h p.i. showed that the two 99mTc-labeled compounds showed varying uptake in receptor expressing organs, stomach and pancreas (1.3–10.4% IA/g), as well as kidneys, the main route of excretion (7.8–19.9% IA/g). The tumor uptake in A431-CCK2R xenografts was 24.75 ± 4.38% IA/g for [99mTc]Tc-HYNIC-MGS5 and 42.48 ± 6.99% IA/g for [99mTc]Tc-HYNIC-MGS11 at 4 h p.i., whereas the tumor-to-kidney ratio was comparable (2.6–3.3). On demand availability and potential application for radioguided surgery of a 99mTc-labeled minigastrin analog support the further evaluation of these highly promising new compounds. Full article
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