64Cu-labeled somatostatin analogues conjugated with cross-bridged phosphonate-based chelators via strain-promoted click chemistry for PET imaging: In silico through in vivo studies

Zhengxin Cai, Qin Ouyang, Dexing Zeng, Kim N. Nguyen, Jalpa Modi, Lirong Wang, Alexander G. White, Buck E. Rogers, Xiang Qun Xie, Carolyn J. Anderson

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr3-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P-DBCO-Y3- TATE (AP) and CB-TE1K1P-PEG4-DBCO-Y3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with Kd values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues.

Original languageEnglish (US)
Pages (from-to)6019-6029
Number of pages11
JournalJournal of Medicinal Chemistry
Volume57
Issue number14
DOIs
StatePublished - Jul 24 2014
Externally publishedYes

Fingerprint

Click Chemistry
Organophosphonates
Chelating Agents
Somatostatin
Computer Simulation
Alkynes
Neuroendocrine Tumors
Azides
Radiopharmaceuticals
Cycloaddition Reaction
G-Protein-Coupled Receptors
Amides
Copper
Pharmacokinetics
somatostatin receptor 2

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

64Cu-labeled somatostatin analogues conjugated with cross-bridged phosphonate-based chelators via strain-promoted click chemistry for PET imaging : In silico through in vivo studies. / Cai, Zhengxin; Ouyang, Qin; Zeng, Dexing; Nguyen, Kim N.; Modi, Jalpa; Wang, Lirong; White, Alexander G.; Rogers, Buck E.; Xie, Xiang Qun; Anderson, Carolyn J.

In: Journal of Medicinal Chemistry, Vol. 57, No. 14, 24.07.2014, p. 6019-6029.

Research output: Contribution to journalArticle

Cai, Zhengxin ; Ouyang, Qin ; Zeng, Dexing ; Nguyen, Kim N. ; Modi, Jalpa ; Wang, Lirong ; White, Alexander G. ; Rogers, Buck E. ; Xie, Xiang Qun ; Anderson, Carolyn J. / 64Cu-labeled somatostatin analogues conjugated with cross-bridged phosphonate-based chelators via strain-promoted click chemistry for PET imaging : In silico through in vivo studies. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 14. pp. 6019-6029.
@article{01488f64d2e543c399b5cbec29c3a509,
title = "64Cu-labeled somatostatin analogues conjugated with cross-bridged phosphonate-based chelators via strain-promoted click chemistry for PET imaging: In silico through in vivo studies",
abstract = "Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr3-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P-DBCO-Y3- TATE (AP) and CB-TE1K1P-PEG4-DBCO-Y3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with Kd values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues.",
author = "Zhengxin Cai and Qin Ouyang and Dexing Zeng and Nguyen, {Kim N.} and Jalpa Modi and Lirong Wang and White, {Alexander G.} and Rogers, {Buck E.} and Xie, {Xiang Qun} and Anderson, {Carolyn J.}",
year = "2014",
month = "7",
day = "24",
doi = "10.1021/jm500416f",
language = "English (US)",
volume = "57",
pages = "6019--6029",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "14",

}

TY - JOUR

T1 - 64Cu-labeled somatostatin analogues conjugated with cross-bridged phosphonate-based chelators via strain-promoted click chemistry for PET imaging

T2 - In silico through in vivo studies

AU - Cai, Zhengxin

AU - Ouyang, Qin

AU - Zeng, Dexing

AU - Nguyen, Kim N.

AU - Modi, Jalpa

AU - Wang, Lirong

AU - White, Alexander G.

AU - Rogers, Buck E.

AU - Xie, Xiang Qun

AU - Anderson, Carolyn J.

PY - 2014/7/24

Y1 - 2014/7/24

N2 - Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr3-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P-DBCO-Y3- TATE (AP) and CB-TE1K1P-PEG4-DBCO-Y3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with Kd values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues.

AB - Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr3-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P-DBCO-Y3- TATE (AP) and CB-TE1K1P-PEG4-DBCO-Y3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with Kd values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues.

UR - http://www.scopus.com/inward/record.url?scp=84904976127&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84904976127&partnerID=8YFLogxK

U2 - 10.1021/jm500416f

DO - 10.1021/jm500416f

M3 - Article

C2 - 24983404

AN - SCOPUS:84904976127

VL - 57

SP - 6019

EP - 6029

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 14

ER -