64Cu-labeled 2-(diphenylphosphoryl)ethyldiphenylphosphonium cations as highly selective tumor imaging agents

Effects of linkers and chelates on radiotracer biodistribution characteristics

Chang Tong Yang, Young Seung Kim, Jianjun Wang, Lijun Wang, Jiyun Shi, Zi Bo Li, Xiaoyuan Chen, Ming Fan, Jian-Jian Li, Shuang Liu

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Radiolabeled organic cations, such as triphenylphosphonium (TPP), represents a new class of radiotracers for imaging cancers and the transport function of multidrug resistance P-glycoproteins (particularly MDR1 Pgp) by single photon emission computed tomography (SPECT) or positron emission tomography (PET). This report presents the synthesis and biological evaluation of 64Cu-labeled 2-(diphenylphosphoryl)ethyldiphenylphosphonium (TPEP) cations as novel PET radiotracers for tumor imaging. Biodistribution studies were performed using the athymic nude mice bearing subcutaneous U87MG human glioma xenografts to explore the impact of linkers, bifunctional chelators (BFCs), and chelates on biodistribution characteristics of the 64Cu-labeled TPEP cations. Metabolism studies were carried out using normal athymic nude mice to determine the metabolic stability of four 64Cu radiotracers. It was found that most 64Cu radiotracers described in this study have significant advantages over 99mTc-Sestamibi for their high tumor/heart and tumor/muscle ratios. Both BFCs and linkers have significant impact on biological properties of 64Cu-labeled TPEP cations. For example, 64Cu(DOSA-Xy-TPEP) has much lower liver uptake and better tumor/liver ratios than 64Cu(DO3A-xy-TPP), suggesting that TPEP is a better mitochondrion-targeting molecule than TPP. Replacing DO3A with DO2A results in 64Cu(DO2A-xy-TPEP)+, which has a lower tumor uptake than 64Cu(DO3A-xy-TPEP). Substitution of DO3A with NOTA-Bn leads to a significant decrease in tumor uptake for 64Cu(NOTA-Bn-Xy-TPEP). The use of DOTA-Bn to replace DO3A has little impact on the tumor uptake, but the tumor/liver ratio of 64Cu(DOTA-Bn-Xy-TPEP)- is not as good as that of 64Cu(DO3A-xy-TPEP), probably due to the aromatic benzene ring in DOTA-Bn. Addition of an extra acetamido group in 64Cu(DOTA- xy-TPEP) results in a lower liver uptake, but tumor/liver ratios of 64Cu(DOTA-xy-TPEP) and 64Cu(DO3 A-xy-TPEP) are comparable due to a faster tumor washout of 64Cu(DOTA-xy-TPEP). Substitution of xylene with the PEG2 linker also leads to a significant reduction in both tumor and liver uptake. MicroPET imaging studies on 64Cu(DO3A- Xy-TPEP) in athymic nude mice bearing U87MG glioma xenografts showed that the tumor was clearly visualized as early as 1 h postinjection with very high T/B contrast. There was very little metabolite (<2%) detectable in the urine and feces samples for 64Cu(DO3A-xy-TPEP),64Cu(DOTA-Bn-xy-TPEP) -, and 64Cu(NOTA-Bn-xy-TPEP). Considering both tumor uptake and T/B ratios (particularly tumor/heart, tumor/liver, and tumor/muscle), it was concluded that 64Cu(DOSA-xy-TPEP) is a promising PET radiotracer for imaging the MDR-negative tumors.

Original languageEnglish (US)
Pages (from-to)2008-2022
Number of pages15
JournalBioconjugate Chemistry
Volume19
Issue number10
DOIs
StatePublished - Oct 2008
Externally publishedYes

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Cations
Tumors
Positive ions
Imaging techniques
Neoplasms
Liver
Nude Mice
Positron emission tomography
Bearings (structural)
Positron-Emission Tomography
Heart Neoplasms
Chelating Agents
Heterografts
Glioma
Muscle
Substitution reactions
P-Glycoproteins
Technetium Tc 99m Sestamibi
Single photon emission computed tomography
Xylenes

ASJC Scopus subject areas

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

Cite this

64Cu-labeled 2-(diphenylphosphoryl)ethyldiphenylphosphonium cations as highly selective tumor imaging agents : Effects of linkers and chelates on radiotracer biodistribution characteristics. / Yang, Chang Tong; Kim, Young Seung; Wang, Jianjun; Wang, Lijun; Shi, Jiyun; Li, Zi Bo; Chen, Xiaoyuan; Fan, Ming; Li, Jian-Jian; Liu, Shuang.

In: Bioconjugate Chemistry, Vol. 19, No. 10, 10.2008, p. 2008-2022.

Research output: Contribution to journalArticle

Yang, Chang Tong ; Kim, Young Seung ; Wang, Jianjun ; Wang, Lijun ; Shi, Jiyun ; Li, Zi Bo ; Chen, Xiaoyuan ; Fan, Ming ; Li, Jian-Jian ; Liu, Shuang. / 64Cu-labeled 2-(diphenylphosphoryl)ethyldiphenylphosphonium cations as highly selective tumor imaging agents : Effects of linkers and chelates on radiotracer biodistribution characteristics. In: Bioconjugate Chemistry. 2008 ; Vol. 19, No. 10. pp. 2008-2022.
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abstract = "Radiolabeled organic cations, such as triphenylphosphonium (TPP), represents a new class of radiotracers for imaging cancers and the transport function of multidrug resistance P-glycoproteins (particularly MDR1 Pgp) by single photon emission computed tomography (SPECT) or positron emission tomography (PET). This report presents the synthesis and biological evaluation of 64Cu-labeled 2-(diphenylphosphoryl)ethyldiphenylphosphonium (TPEP) cations as novel PET radiotracers for tumor imaging. Biodistribution studies were performed using the athymic nude mice bearing subcutaneous U87MG human glioma xenografts to explore the impact of linkers, bifunctional chelators (BFCs), and chelates on biodistribution characteristics of the 64Cu-labeled TPEP cations. Metabolism studies were carried out using normal athymic nude mice to determine the metabolic stability of four 64Cu radiotracers. It was found that most 64Cu radiotracers described in this study have significant advantages over 99mTc-Sestamibi for their high tumor/heart and tumor/muscle ratios. Both BFCs and linkers have significant impact on biological properties of 64Cu-labeled TPEP cations. For example, 64Cu(DOSA-Xy-TPEP) has much lower liver uptake and better tumor/liver ratios than 64Cu(DO3A-xy-TPP), suggesting that TPEP is a better mitochondrion-targeting molecule than TPP. Replacing DO3A with DO2A results in 64Cu(DO2A-xy-TPEP)+, which has a lower tumor uptake than 64Cu(DO3A-xy-TPEP). Substitution of DO3A with NOTA-Bn leads to a significant decrease in tumor uptake for 64Cu(NOTA-Bn-Xy-TPEP). The use of DOTA-Bn to replace DO3A has little impact on the tumor uptake, but the tumor/liver ratio of 64Cu(DOTA-Bn-Xy-TPEP)- is not as good as that of 64Cu(DO3A-xy-TPEP), probably due to the aromatic benzene ring in DOTA-Bn. Addition of an extra acetamido group in 64Cu(DOTA- xy-TPEP) results in a lower liver uptake, but tumor/liver ratios of 64Cu(DOTA-xy-TPEP) and 64Cu(DO3 A-xy-TPEP) are comparable due to a faster tumor washout of 64Cu(DOTA-xy-TPEP). Substitution of xylene with the PEG2 linker also leads to a significant reduction in both tumor and liver uptake. MicroPET imaging studies on 64Cu(DO3A- Xy-TPEP) in athymic nude mice bearing U87MG glioma xenografts showed that the tumor was clearly visualized as early as 1 h postinjection with very high T/B contrast. There was very little metabolite (<2{\%}) detectable in the urine and feces samples for 64Cu(DO3A-xy-TPEP),64Cu(DOTA-Bn-xy-TPEP) -, and 64Cu(NOTA-Bn-xy-TPEP). Considering both tumor uptake and T/B ratios (particularly tumor/heart, tumor/liver, and tumor/muscle), it was concluded that 64Cu(DOSA-xy-TPEP) is a promising PET radiotracer for imaging the MDR-negative tumors.",
author = "Yang, {Chang Tong} and Kim, {Young Seung} and Jianjun Wang and Lijun Wang and Jiyun Shi and Li, {Zi Bo} and Xiaoyuan Chen and Ming Fan and Jian-Jian Li and Shuang Liu",
year = "2008",
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TY - JOUR

T1 - 64Cu-labeled 2-(diphenylphosphoryl)ethyldiphenylphosphonium cations as highly selective tumor imaging agents

T2 - Effects of linkers and chelates on radiotracer biodistribution characteristics

AU - Yang, Chang Tong

AU - Kim, Young Seung

AU - Wang, Jianjun

AU - Wang, Lijun

AU - Shi, Jiyun

AU - Li, Zi Bo

AU - Chen, Xiaoyuan

AU - Fan, Ming

AU - Li, Jian-Jian

AU - Liu, Shuang

PY - 2008/10

Y1 - 2008/10

N2 - Radiolabeled organic cations, such as triphenylphosphonium (TPP), represents a new class of radiotracers for imaging cancers and the transport function of multidrug resistance P-glycoproteins (particularly MDR1 Pgp) by single photon emission computed tomography (SPECT) or positron emission tomography (PET). This report presents the synthesis and biological evaluation of 64Cu-labeled 2-(diphenylphosphoryl)ethyldiphenylphosphonium (TPEP) cations as novel PET radiotracers for tumor imaging. Biodistribution studies were performed using the athymic nude mice bearing subcutaneous U87MG human glioma xenografts to explore the impact of linkers, bifunctional chelators (BFCs), and chelates on biodistribution characteristics of the 64Cu-labeled TPEP cations. Metabolism studies were carried out using normal athymic nude mice to determine the metabolic stability of four 64Cu radiotracers. It was found that most 64Cu radiotracers described in this study have significant advantages over 99mTc-Sestamibi for their high tumor/heart and tumor/muscle ratios. Both BFCs and linkers have significant impact on biological properties of 64Cu-labeled TPEP cations. For example, 64Cu(DOSA-Xy-TPEP) has much lower liver uptake and better tumor/liver ratios than 64Cu(DO3A-xy-TPP), suggesting that TPEP is a better mitochondrion-targeting molecule than TPP. Replacing DO3A with DO2A results in 64Cu(DO2A-xy-TPEP)+, which has a lower tumor uptake than 64Cu(DO3A-xy-TPEP). Substitution of DO3A with NOTA-Bn leads to a significant decrease in tumor uptake for 64Cu(NOTA-Bn-Xy-TPEP). The use of DOTA-Bn to replace DO3A has little impact on the tumor uptake, but the tumor/liver ratio of 64Cu(DOTA-Bn-Xy-TPEP)- is not as good as that of 64Cu(DO3A-xy-TPEP), probably due to the aromatic benzene ring in DOTA-Bn. Addition of an extra acetamido group in 64Cu(DOTA- xy-TPEP) results in a lower liver uptake, but tumor/liver ratios of 64Cu(DOTA-xy-TPEP) and 64Cu(DO3 A-xy-TPEP) are comparable due to a faster tumor washout of 64Cu(DOTA-xy-TPEP). Substitution of xylene with the PEG2 linker also leads to a significant reduction in both tumor and liver uptake. MicroPET imaging studies on 64Cu(DO3A- Xy-TPEP) in athymic nude mice bearing U87MG glioma xenografts showed that the tumor was clearly visualized as early as 1 h postinjection with very high T/B contrast. There was very little metabolite (<2%) detectable in the urine and feces samples for 64Cu(DO3A-xy-TPEP),64Cu(DOTA-Bn-xy-TPEP) -, and 64Cu(NOTA-Bn-xy-TPEP). Considering both tumor uptake and T/B ratios (particularly tumor/heart, tumor/liver, and tumor/muscle), it was concluded that 64Cu(DOSA-xy-TPEP) is a promising PET radiotracer for imaging the MDR-negative tumors.

AB - Radiolabeled organic cations, such as triphenylphosphonium (TPP), represents a new class of radiotracers for imaging cancers and the transport function of multidrug resistance P-glycoproteins (particularly MDR1 Pgp) by single photon emission computed tomography (SPECT) or positron emission tomography (PET). This report presents the synthesis and biological evaluation of 64Cu-labeled 2-(diphenylphosphoryl)ethyldiphenylphosphonium (TPEP) cations as novel PET radiotracers for tumor imaging. Biodistribution studies were performed using the athymic nude mice bearing subcutaneous U87MG human glioma xenografts to explore the impact of linkers, bifunctional chelators (BFCs), and chelates on biodistribution characteristics of the 64Cu-labeled TPEP cations. Metabolism studies were carried out using normal athymic nude mice to determine the metabolic stability of four 64Cu radiotracers. It was found that most 64Cu radiotracers described in this study have significant advantages over 99mTc-Sestamibi for their high tumor/heart and tumor/muscle ratios. Both BFCs and linkers have significant impact on biological properties of 64Cu-labeled TPEP cations. For example, 64Cu(DOSA-Xy-TPEP) has much lower liver uptake and better tumor/liver ratios than 64Cu(DO3A-xy-TPP), suggesting that TPEP is a better mitochondrion-targeting molecule than TPP. Replacing DO3A with DO2A results in 64Cu(DO2A-xy-TPEP)+, which has a lower tumor uptake than 64Cu(DO3A-xy-TPEP). Substitution of DO3A with NOTA-Bn leads to a significant decrease in tumor uptake for 64Cu(NOTA-Bn-Xy-TPEP). The use of DOTA-Bn to replace DO3A has little impact on the tumor uptake, but the tumor/liver ratio of 64Cu(DOTA-Bn-Xy-TPEP)- is not as good as that of 64Cu(DO3A-xy-TPEP), probably due to the aromatic benzene ring in DOTA-Bn. Addition of an extra acetamido group in 64Cu(DOTA- xy-TPEP) results in a lower liver uptake, but tumor/liver ratios of 64Cu(DOTA-xy-TPEP) and 64Cu(DO3 A-xy-TPEP) are comparable due to a faster tumor washout of 64Cu(DOTA-xy-TPEP). Substitution of xylene with the PEG2 linker also leads to a significant reduction in both tumor and liver uptake. MicroPET imaging studies on 64Cu(DO3A- Xy-TPEP) in athymic nude mice bearing U87MG glioma xenografts showed that the tumor was clearly visualized as early as 1 h postinjection with very high T/B contrast. There was very little metabolite (<2%) detectable in the urine and feces samples for 64Cu(DO3A-xy-TPEP),64Cu(DOTA-Bn-xy-TPEP) -, and 64Cu(NOTA-Bn-xy-TPEP). Considering both tumor uptake and T/B ratios (particularly tumor/heart, tumor/liver, and tumor/muscle), it was concluded that 64Cu(DOSA-xy-TPEP) is a promising PET radiotracer for imaging the MDR-negative tumors.

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