Synthesis and Evaluation of New Bifunctional Chelators with Phosphonic Acid Arms for Gallium-68 Based PET Imaging in Melanoma

Yongkang Gai, Lingyi Sun, Xiaoli Lan, Dexing Zeng, Guangya Xiang, Xiang Ma

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Due to the increasing use of generator-produced radiometal Gallium-68 (68Ga) in positron-emission tomography/computed tomography (PET/CT), reliable bifunctional chelators that can efficiently incorporate 68Ga3+ into biomolecules are highly desirable. In this study, we synthesized two new bifunctional chelators bearing one or two phosphonic acid functional groups, named p-SCN-PhPr-NE2A1P and p-SCN-PhPr-NE2P1A, with the aim of enabling facile production of 68Ga-based radiopharmaceuticals. Both chelators were successfully conjugated to LLP2A-PEG4, a very late antigen-4 (VLA-4) targeting peptidomimetic ligand, to evaluate their application in 68Ga-based PET imaging. NE2P1A-PEG4-LLP2A exhibited the highest 68Ga3+ binding ability with molar activity of 37 MBq/nmol under mild temperature and neutral pH. Excellent serum stability of 68Ga-NE2P1A-PEG4-LLP2A was observed, which was consistent with the result obtained from density functional theory calculation. The in vitro cell study showed that 68Ga-NE2P1A-PEG4-LLP2A had significantly longer retention in B16F10 cells comparing to the reported retention of 64Cu-NE3TA-PEG4-LLP2A, although the uptake was relatively lower. In the biodistribution and micro-PET/CT imaging studies, high tumor uptake and low background were observed after 68Ga-NE2P1A-PEG4-LLP2A was injected into mice bearing B16F10 tumor xenografts, making it a highly promising radiotracer for noninvasive imaging of VLA-4 receptors overexpressed in melanoma.

Original languageEnglish (US)
Pages (from-to)3483-3494
Number of pages12
JournalBioconjugate Chemistry
Volume29
Issue number10
DOIs
StatePublished - Oct 17 2018

Fingerprint

Gallium
Bearings (structural)
Chelating Agents
Integrin alpha4beta1
Melanoma
Positron emission tomography
Arm
Antigens
Imaging techniques
Very Late Antigen Receptors
Tomography
Acids
Tumors
Peptidomimetics
Radiopharmaceuticals
Biomolecules
Heterografts
Functional groups
Density functional theory
Neoplasms

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry

Cite this

Synthesis and Evaluation of New Bifunctional Chelators with Phosphonic Acid Arms for Gallium-68 Based PET Imaging in Melanoma. / Gai, Yongkang; Sun, Lingyi; Lan, Xiaoli; Zeng, Dexing; Xiang, Guangya; Ma, Xiang.

In: Bioconjugate Chemistry, Vol. 29, No. 10, 17.10.2018, p. 3483-3494.

Research output: Contribution to journalArticle

Gai, Yongkang ; Sun, Lingyi ; Lan, Xiaoli ; Zeng, Dexing ; Xiang, Guangya ; Ma, Xiang. / Synthesis and Evaluation of New Bifunctional Chelators with Phosphonic Acid Arms for Gallium-68 Based PET Imaging in Melanoma. In: Bioconjugate Chemistry. 2018 ; Vol. 29, No. 10. pp. 3483-3494.
@article{2713c5bb8d4c42fea928cef7c1ddda68,
title = "Synthesis and Evaluation of New Bifunctional Chelators with Phosphonic Acid Arms for Gallium-68 Based PET Imaging in Melanoma",
abstract = "Due to the increasing use of generator-produced radiometal Gallium-68 (68Ga) in positron-emission tomography/computed tomography (PET/CT), reliable bifunctional chelators that can efficiently incorporate 68Ga3+ into biomolecules are highly desirable. In this study, we synthesized two new bifunctional chelators bearing one or two phosphonic acid functional groups, named p-SCN-PhPr-NE2A1P and p-SCN-PhPr-NE2P1A, with the aim of enabling facile production of 68Ga-based radiopharmaceuticals. Both chelators were successfully conjugated to LLP2A-PEG4, a very late antigen-4 (VLA-4) targeting peptidomimetic ligand, to evaluate their application in 68Ga-based PET imaging. NE2P1A-PEG4-LLP2A exhibited the highest 68Ga3+ binding ability with molar activity of 37 MBq/nmol under mild temperature and neutral pH. Excellent serum stability of 68Ga-NE2P1A-PEG4-LLP2A was observed, which was consistent with the result obtained from density functional theory calculation. The in vitro cell study showed that 68Ga-NE2P1A-PEG4-LLP2A had significantly longer retention in B16F10 cells comparing to the reported retention of 64Cu-NE3TA-PEG4-LLP2A, although the uptake was relatively lower. In the biodistribution and micro-PET/CT imaging studies, high tumor uptake and low background were observed after 68Ga-NE2P1A-PEG4-LLP2A was injected into mice bearing B16F10 tumor xenografts, making it a highly promising radiotracer for noninvasive imaging of VLA-4 receptors overexpressed in melanoma.",
author = "Yongkang Gai and Lingyi Sun and Xiaoli Lan and Dexing Zeng and Guangya Xiang and Xiang Ma",
year = "2018",
month = "10",
day = "17",
doi = "10.1021/acs.bioconjchem.8b00642",
language = "English (US)",
volume = "29",
pages = "3483--3494",
journal = "Bioconjugate Chemistry",
issn = "1043-1802",
publisher = "American Chemical Society",
number = "10",

}

TY - JOUR

T1 - Synthesis and Evaluation of New Bifunctional Chelators with Phosphonic Acid Arms for Gallium-68 Based PET Imaging in Melanoma

AU - Gai, Yongkang

AU - Sun, Lingyi

AU - Lan, Xiaoli

AU - Zeng, Dexing

AU - Xiang, Guangya

AU - Ma, Xiang

PY - 2018/10/17

Y1 - 2018/10/17

N2 - Due to the increasing use of generator-produced radiometal Gallium-68 (68Ga) in positron-emission tomography/computed tomography (PET/CT), reliable bifunctional chelators that can efficiently incorporate 68Ga3+ into biomolecules are highly desirable. In this study, we synthesized two new bifunctional chelators bearing one or two phosphonic acid functional groups, named p-SCN-PhPr-NE2A1P and p-SCN-PhPr-NE2P1A, with the aim of enabling facile production of 68Ga-based radiopharmaceuticals. Both chelators were successfully conjugated to LLP2A-PEG4, a very late antigen-4 (VLA-4) targeting peptidomimetic ligand, to evaluate their application in 68Ga-based PET imaging. NE2P1A-PEG4-LLP2A exhibited the highest 68Ga3+ binding ability with molar activity of 37 MBq/nmol under mild temperature and neutral pH. Excellent serum stability of 68Ga-NE2P1A-PEG4-LLP2A was observed, which was consistent with the result obtained from density functional theory calculation. The in vitro cell study showed that 68Ga-NE2P1A-PEG4-LLP2A had significantly longer retention in B16F10 cells comparing to the reported retention of 64Cu-NE3TA-PEG4-LLP2A, although the uptake was relatively lower. In the biodistribution and micro-PET/CT imaging studies, high tumor uptake and low background were observed after 68Ga-NE2P1A-PEG4-LLP2A was injected into mice bearing B16F10 tumor xenografts, making it a highly promising radiotracer for noninvasive imaging of VLA-4 receptors overexpressed in melanoma.

AB - Due to the increasing use of generator-produced radiometal Gallium-68 (68Ga) in positron-emission tomography/computed tomography (PET/CT), reliable bifunctional chelators that can efficiently incorporate 68Ga3+ into biomolecules are highly desirable. In this study, we synthesized two new bifunctional chelators bearing one or two phosphonic acid functional groups, named p-SCN-PhPr-NE2A1P and p-SCN-PhPr-NE2P1A, with the aim of enabling facile production of 68Ga-based radiopharmaceuticals. Both chelators were successfully conjugated to LLP2A-PEG4, a very late antigen-4 (VLA-4) targeting peptidomimetic ligand, to evaluate their application in 68Ga-based PET imaging. NE2P1A-PEG4-LLP2A exhibited the highest 68Ga3+ binding ability with molar activity of 37 MBq/nmol under mild temperature and neutral pH. Excellent serum stability of 68Ga-NE2P1A-PEG4-LLP2A was observed, which was consistent with the result obtained from density functional theory calculation. The in vitro cell study showed that 68Ga-NE2P1A-PEG4-LLP2A had significantly longer retention in B16F10 cells comparing to the reported retention of 64Cu-NE3TA-PEG4-LLP2A, although the uptake was relatively lower. In the biodistribution and micro-PET/CT imaging studies, high tumor uptake and low background were observed after 68Ga-NE2P1A-PEG4-LLP2A was injected into mice bearing B16F10 tumor xenografts, making it a highly promising radiotracer for noninvasive imaging of VLA-4 receptors overexpressed in melanoma.

UR - http://www.scopus.com/inward/record.url?scp=85054133087&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054133087&partnerID=8YFLogxK

U2 - 10.1021/acs.bioconjchem.8b00642

DO - 10.1021/acs.bioconjchem.8b00642

M3 - Article

VL - 29

SP - 3483

EP - 3494

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

SN - 1043-1802

IS - 10

ER -