A New Turn in Peptide-Based Imaging Agents: Foldamers Afford Improved Theranostics Targeting Cholecystokinin-2 Receptor-Positive Cancer

Corlett, Alicia; Sani, Marc‐Antoine; Zuylekom, Jessica Van; C, Ang; Guggenberg, Elisabeth von; Cullinane, Carleen; Blyth, Benjamin J.; Hicks, Rodney J.; Roselt, Peter; Thompson, Phillip E.; Hutton, Craig A.; Haskali, Mohammad B.

doi:10.1021/acs.jmedchem.0c02213

Cited by 14 publications

(38 citation statements)

References 59 publications

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“…It is important to note that there were no large discrepancies between the metabolic rate of these peptides and previous iterations labeled with gallium-68 . In fact, they followed similar rates of degradation, and because these peptides were labeled with the longer-lived lutetium-177, we were able to follow their fate over a much longer period.…”

Section: Discussionmentioning

confidence: 80%

“…Herein, we describe the development of lutetium-177 ( 177 Lu)-labeled CCK 2 R binding peptides exhibiting the β-hairpin structure with exquisite chemical and pharmacological properties . These 177 Lu-labeled peptides were analyzed both in vitro and in vivo to characterize their pharmacokinetic properties for the identification of a lead candidate for use in PRRT against tumors overexpressing CCK 2 R.…”

Section: Introductionmentioning

confidence: 99%

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Development of Highly Potent Clinical Candidates for Theranostic Applications against Cholecystokinin-2 Receptor Positive Cancers

et al. 2023

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Peptide receptor radionuclide therapy (PRRT) is a promising form of systemic radiation therapy designed to eradicate cancer. Cholecystokinin-2 receptor (CCK 2 R) is an important molecular target that is highly expressed in a range of cancers. This study describes the synthesis and in vivo characterization of a novel series of 177 Lu-labeled peptides ([ 177 Lu]Lu-2b−4b) in comparison with the reference CCK 2 R-targeting peptide CP04 ([ 177 Lu]Lu-1b).[ 177 Lu]Lu-1b-4b showed high chemical purity (HPLC ≥ 94%), low Log D 7.4 (−4.09 to −4.55) with strong binding affinity to CCK 2 R (K D 0.097−1.61 nM), and relatively high protein binding (55.6−80.2%) and internalization (40−67%). Biodistribution studies of the novel 177 Lu-labeled peptides in tumors (AR42J and A431-CCK 2 R) showed uptake one-to eight-fold greater than the reference compound CP04 at 1, 24, and 48 h. Rapid clearance and high tumor uptake and retention were established for [ 177 Lu]Lu-2b−4b, making these compounds excellent candidates for theranostic applications against CCK 2 R-expressing tumors.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Development of Highly Potent Clinical Candidates for Theranostic Applications against Cholecystokinin-2 Receptor Positive Cancers

et al. 2023

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“…Radiolabeled peptides to be used in the diagnosis and therapy of various malignancies need to fulfill certain requirements such as robust and reproducible labeling with radioisotopes, specific targeting of receptors and high resistance against enzymatic catabolism [ 10 ]. Within the last years, the development of a radiolabeled gastrin derivative fulfilling this criterion has attracted increasing attention [ 10 , 12 , 15 , 19 , 20 ]. Among various tumor entities that can be considered for CCK2R targeting, patients with advanced MTC could especially benefit from this new diagnostic and therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

Automated Synthesis of 68Ga-Labeled DOTA-MGS8 and Preclinical Characterization of Cholecystokinin-2 Receptor Targeting

et al. 2022

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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.

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“…The introduction of the above C-terminal amino acid substitutions was also investigated for CP04 in combination with additional N-methylation of Gly in position 9. Evaluation of the biodistribution profile of the 68 Ga-labeled compounds in athymic nude mice bearing AR42J xenografts revealed a similar increase in tumor uptake, but resulted in a higher kidney retention [ 42 ].…”

Section: Current Radiopharmaceutical Developmentmentioning

confidence: 99%

Update on Preclinical Development and Clinical Translation of Cholecystokinin-2 Receptor Targeting Radiopharmaceuticals

Guggenberg

Peitl

Rottenburger

et al. 2021

Cancers

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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.

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A New Turn in Peptide-Based Imaging Agents: Foldamers Afford Improved Theranostics Targeting Cholecystokinin-2 Receptor-Positive Cancer

Cited by 14 publications

References 59 publications

Development of Highly Potent Clinical Candidates for Theranostic Applications against Cholecystokinin-2 Receptor Positive Cancers

Development of Highly Potent Clinical Candidates for Theranostic Applications against Cholecystokinin-2 Receptor Positive Cancers

Automated Synthesis of 68Ga-Labeled DOTA-MGS8 and Preclinical Characterization of Cholecystokinin-2 Receptor Targeting

Update on Preclinical Development and Clinical Translation of Cholecystokinin-2 Receptor Targeting Radiopharmaceuticals

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