Nonpeptidic Z360-Analogs Tagged with Trivalent Radiometals as Anti-CCK2R Cancer Theranostic Agents: A Preclinical Study

Berthold A. Nock; Panagiotis Kanellopoulos; Oleg G. Chepurny; Maritina Rouchota; George Loudos; George G. Holz; Eric P. Krenning; Theodosia Maina

doi:10.3390/pharmaceutics14030666

Nonpeptidic Z360-Analogs Tagged with Trivalent Radiometals as Anti-CCK₂R Cancer Theranostic Agents: A Preclinical Study

Berthold A. Nock, Panagiotis Kanellopoulos, Oleg G. Chepurny, Maritina Rouchota, George Loudos, George G. Holz, Eric P. Krenning, Theodosia Maina^*

^*Corresponding author for this work

Erasmus MC other

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

(1) Background: Theranostic approaches in the management of cholecystokinin subtype 2 receptor (CCK₂R)-positive tumors include radiolabeled gastrin and CCK motifs. Moving toward antagonist-based CCK₂R-radioligands instead, we herein present three analogs of the nonpeptidic CCK₂R-antagonist Z360, GAS1/2/3. Each was conjugated to a different chelator (DOTA, NODAGA or DOTAGA) for labeling with medically relevant trivalent radiometals (e.g., Ga-68, In-111, Lu-177) for potential use as anti-CCK₂R cancer agents; (2) Methods: The in vitro properties of the thee analogs were compared in stably transfected HEK293-CCK₂R cells. Biodistribution profiles were compared in SCID mice bearing twin HEK293-CCK₂R and wtHEK293 tumors; (3) Results: The GAS1/2/3 analogs displayed high CCK₂R-affinity (lower nM-range). The radioligands were fairly stable in vivo and selectively targeted the HEK293-CCK₂R, but not the CCK₂R-negative wtHEK293 tumors in mice. Their overall pharmacokinetic profile was found strongly dependent on the radiometal-chelate. Results could be visualized by SPECT/CT for the [¹¹¹ In]In-analogs; (4) Conclusions: The present study highlighted the high impact of the radiometal-chelate on the end-pharmacokinetics of a new series of Z360-based radioligands, revealing candidates with promising properties for clinical translation. It also provided the impetus for the development of a new class of nonpeptidic radioligands for CCK₂R-targeted theranostics of human cancer.

Original language	English
Article number	666
Journal	Pharmaceutics
Volume	14
Issue number	3
DOIs	https://doi.org/10.3390/pharmaceutics14030666
Publication status	Published - 18 Mar 2022

Bibliographical note

Funding Information:
Funding: This research was funded by the Greek General Secretariat for Research and Technology and the European Regional Development Fund under the Action “Development Grants for Research Institutions—KRIPIS” of OPCE II (to T.M. and B.A.N.) and by NIH R01DK069575; R01DK122332 (to G.G.H.).

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© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

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Cite this

@article{d8f9ff449e4640edb75baf4dcf354dc1,

title = "Nonpeptidic Z360-Analogs Tagged with Trivalent Radiometals as Anti-CCK2R Cancer Theranostic Agents: A Preclinical Study",

abstract = "(1) Background: Theranostic approaches in the management of cholecystokinin subtype 2 receptor (CCK2R)-positive tumors include radiolabeled gastrin and CCK motifs. Moving toward antagonist-based CCK2R-radioligands instead, we herein present three analogs of the nonpeptidic CCK2R-antagonist Z360, GAS1/2/3. Each was conjugated to a different chelator (DOTA, NODAGA or DOTAGA) for labeling with medically relevant trivalent radiometals (e.g., Ga-68, In-111, Lu-177) for potential use as anti-CCK2R cancer agents; (2) Methods: The in vitro properties of the thee analogs were compared in stably transfected HEK293-CCK2R cells. Biodistribution profiles were compared in SCID mice bearing twin HEK293-CCK2R and wtHEK293 tumors; (3) Results: The GAS1/2/3 analogs displayed high CCK2R-affinity (lower nM-range). The radioligands were fairly stable in vivo and selectively targeted the HEK293-CCK2R, but not the CCK2R-negative wtHEK293 tumors in mice. Their overall pharmacokinetic profile was found strongly dependent on the radiometal-chelate. Results could be visualized by SPECT/CT for the [111 In]In-analogs; (4) Conclusions: The present study highlighted the high impact of the radiometal-chelate on the end-pharmacokinetics of a new series of Z360-based radioligands, revealing candidates with promising properties for clinical translation. It also provided the impetus for the development of a new class of nonpeptidic radioligands for CCK2R-targeted theranostics of human cancer.",

author = "Nock, {Berthold A.} and Panagiotis Kanellopoulos and Chepurny, {Oleg G.} and Maritina Rouchota and George Loudos and Holz, {George G.} and Krenning, {Eric P.} and Theodosia Maina",

note = "Funding Information: Funding: This research was funded by the Greek General Secretariat for Research and Technology and the European Regional Development Fund under the Action “Development Grants for Research Institutions—KRIPIS” of OPCE II (to T.M. and B.A.N.) and by NIH R01DK069575; R01DK122332 (to G.G.H.). Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

month = mar,

day = "18",

doi = "10.3390/pharmaceutics14030666",

language = "English",

volume = "14",

journal = "Pharmaceutics",

issn = "1999-4923",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "3",

}

TY - JOUR

T1 - Nonpeptidic Z360-Analogs Tagged with Trivalent Radiometals as Anti-CCK2R Cancer Theranostic Agents

T2 - A Preclinical Study

AU - Nock, Berthold A.

AU - Kanellopoulos, Panagiotis

AU - Chepurny, Oleg G.

AU - Rouchota, Maritina

AU - Loudos, George

AU - Holz, George G.

AU - Krenning, Eric P.

AU - Maina, Theodosia

N1 - Funding Information: Funding: This research was funded by the Greek General Secretariat for Research and Technology and the European Regional Development Fund under the Action “Development Grants for Research Institutions—KRIPIS” of OPCE II (to T.M. and B.A.N.) and by NIH R01DK069575; R01DK122332 (to G.G.H.). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2022/3/18

Y1 - 2022/3/18

N2 - (1) Background: Theranostic approaches in the management of cholecystokinin subtype 2 receptor (CCK2R)-positive tumors include radiolabeled gastrin and CCK motifs. Moving toward antagonist-based CCK2R-radioligands instead, we herein present three analogs of the nonpeptidic CCK2R-antagonist Z360, GAS1/2/3. Each was conjugated to a different chelator (DOTA, NODAGA or DOTAGA) for labeling with medically relevant trivalent radiometals (e.g., Ga-68, In-111, Lu-177) for potential use as anti-CCK2R cancer agents; (2) Methods: The in vitro properties of the thee analogs were compared in stably transfected HEK293-CCK2R cells. Biodistribution profiles were compared in SCID mice bearing twin HEK293-CCK2R and wtHEK293 tumors; (3) Results: The GAS1/2/3 analogs displayed high CCK2R-affinity (lower nM-range). The radioligands were fairly stable in vivo and selectively targeted the HEK293-CCK2R, but not the CCK2R-negative wtHEK293 tumors in mice. Their overall pharmacokinetic profile was found strongly dependent on the radiometal-chelate. Results could be visualized by SPECT/CT for the [111 In]In-analogs; (4) Conclusions: The present study highlighted the high impact of the radiometal-chelate on the end-pharmacokinetics of a new series of Z360-based radioligands, revealing candidates with promising properties for clinical translation. It also provided the impetus for the development of a new class of nonpeptidic radioligands for CCK2R-targeted theranostics of human cancer.

AB - (1) Background: Theranostic approaches in the management of cholecystokinin subtype 2 receptor (CCK2R)-positive tumors include radiolabeled gastrin and CCK motifs. Moving toward antagonist-based CCK2R-radioligands instead, we herein present three analogs of the nonpeptidic CCK2R-antagonist Z360, GAS1/2/3. Each was conjugated to a different chelator (DOTA, NODAGA or DOTAGA) for labeling with medically relevant trivalent radiometals (e.g., Ga-68, In-111, Lu-177) for potential use as anti-CCK2R cancer agents; (2) Methods: The in vitro properties of the thee analogs were compared in stably transfected HEK293-CCK2R cells. Biodistribution profiles were compared in SCID mice bearing twin HEK293-CCK2R and wtHEK293 tumors; (3) Results: The GAS1/2/3 analogs displayed high CCK2R-affinity (lower nM-range). The radioligands were fairly stable in vivo and selectively targeted the HEK293-CCK2R, but not the CCK2R-negative wtHEK293 tumors in mice. Their overall pharmacokinetic profile was found strongly dependent on the radiometal-chelate. Results could be visualized by SPECT/CT for the [111 In]In-analogs; (4) Conclusions: The present study highlighted the high impact of the radiometal-chelate on the end-pharmacokinetics of a new series of Z360-based radioligands, revealing candidates with promising properties for clinical translation. It also provided the impetus for the development of a new class of nonpeptidic radioligands for CCK2R-targeted theranostics of human cancer.

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U2 - 10.3390/pharmaceutics14030666

DO - 10.3390/pharmaceutics14030666

M3 - Article

C2 - 35336041

AN - SCOPUS:85127120123

SN - 1999-4923

VL - 14

JO - Pharmaceutics

JF - Pharmaceutics

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