Assessment of PSMA targeting ligands bearing novel chelates with application to theranostics: Stability and complexation kinetics of 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 +

James M. Kelly, Alejandro Amor-Coarasa, Anastasia Nikolopoulou, Dohyun Kim, Clarence Williams, Shankar Vallabhajosula, John W. Babich

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Introduction Recent successes in the treatment of metastatic castration-resistant prostate cancer (mCRPCa) by systemic endoradiotherapy has sparked renewed interest in developing small molecule ligands targeting prostate-specific membrane antigen (PSMA) and chelators capable of stable complexation of metal radionuclides for imaging and therapy. As the size and coordination number of metals for imaging, such as 68Ga3 +, and for targeted therapy, such as 177Lu3 + and 225Ac3 +, are substantially different, they may show a preference for macrocycles of different denticity. We have prepared three simple conjugates that target PSMA and form radiometal complexes through coordination by either octa-, deca-, or dodecadentate tetraazacyclododecane chelators. The complex formation and metal ion selectivity of these constructs were determined at two relevant temperatures, complex stability was examined in vitro, and tumor targeting was demonstrated in preclinical PCa models with a view towards identifying a candidate with potential value as a theranostic agent for the imaging and therapy of mCRPCa. Methods Three bifunctional chelates with high denticity, including the octadentate chelate DOTA, the decadentate 3p-C-DEPA and a novel dodecadentate analogue of DEPA, were synthesized and conjugated to a glutamate-urea-lysine (EuK) pharmacophore (EuK-DOTA, EuK-107 and EuK-106, respectively) to enable targeting of PSMA. The metal ion selectivity for each construct was determined by incubation at 25 °C and 95 °C with the trivalent radiometals 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 +. PSMA binding affinity was determined by competitive binding using LNCaP cells, while in vivo tumor targeting of the 68Ga-labeled constructs was examined by positron emission tomography (PET) in LNCaP xenograft tumor-bearing mice. Results PMSA affinities (IC50 values) were 13.3 ± 0.9 nM for EuK-DOTA, 18.0 ± 3.7 nM for EuK-107 and 42.6 ± 6.6 nM for EuK-106. EuK-107 and EuK-DOTA proved to rapidly and near quantitatively complex 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 + at 95 °C, with EuK-107 also rapidly complexing 111In3 + and 177Lu3 + at 25 °C. The inability of EuK-106 to chelate 177Lu3 + and 225Ac3 + suggests that size of the cavity of the macrocylic ring may be more critical than the number of donor groups for the chelation of larger radiometals. In vivo, 68Ga-EuK-107 proved to have similar uptake to 68Ga-DKFZ-PSMA-617, a theranostic ligand currently in clinical evaluation, in a PSMA positive xenograft tumor model. Conclusions The broad metal ion selectivity, good in vitro affinity for PSMA and good in vivo tumor targeting suggest that EuK-107, with the 3p-C-DEPA chelator, merits further evaluation as a theranostics construct in prostate cancer.

Original languageEnglish (US)
Pages (from-to)38-46
Number of pages9
JournalNuclear Medicine and Biology
Volume55
DOIs
StatePublished - Dec 2017
Externally publishedYes

Fingerprint

Ligands
Chelating Agents
Metals
Prostatic Neoplasms
Castration
Coordination Complexes
Ions
Neoplasms
Heterografts
Competitive Binding
Therapeutics
Theranostic Nanomedicine
human glutamate carboxypeptidase II
Radionuclide Imaging
Positron-Emission Tomography
Inhibitory Concentration 50
Lysine
Urea
Glutamic Acid
Temperature

Keywords

  • 3p-C-DEPA
  • Bifunctional chelate
  • PET
  • Prostate cancer
  • PSMA
  • Targeted radiotherapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Assessment of PSMA targeting ligands bearing novel chelates with application to theranostics : Stability and complexation kinetics of 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 +. / Kelly, James M.; Amor-Coarasa, Alejandro; Nikolopoulou, Anastasia; Kim, Dohyun; Williams, Clarence; Vallabhajosula, Shankar; Babich, John W.

In: Nuclear Medicine and Biology, Vol. 55, 12.2017, p. 38-46.

Research output: Contribution to journalArticle

Kelly, James M. ; Amor-Coarasa, Alejandro ; Nikolopoulou, Anastasia ; Kim, Dohyun ; Williams, Clarence ; Vallabhajosula, Shankar ; Babich, John W. / Assessment of PSMA targeting ligands bearing novel chelates with application to theranostics : Stability and complexation kinetics of 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 +. In: Nuclear Medicine and Biology. 2017 ; Vol. 55. pp. 38-46.
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abstract = "Introduction Recent successes in the treatment of metastatic castration-resistant prostate cancer (mCRPCa) by systemic endoradiotherapy has sparked renewed interest in developing small molecule ligands targeting prostate-specific membrane antigen (PSMA) and chelators capable of stable complexation of metal radionuclides for imaging and therapy. As the size and coordination number of metals for imaging, such as 68Ga3 +, and for targeted therapy, such as 177Lu3 + and 225Ac3 +, are substantially different, they may show a preference for macrocycles of different denticity. We have prepared three simple conjugates that target PSMA and form radiometal complexes through coordination by either octa-, deca-, or dodecadentate tetraazacyclododecane chelators. The complex formation and metal ion selectivity of these constructs were determined at two relevant temperatures, complex stability was examined in vitro, and tumor targeting was demonstrated in preclinical PCa models with a view towards identifying a candidate with potential value as a theranostic agent for the imaging and therapy of mCRPCa. Methods Three bifunctional chelates with high denticity, including the octadentate chelate DOTA, the decadentate 3p-C-DEPA and a novel dodecadentate analogue of DEPA, were synthesized and conjugated to a glutamate-urea-lysine (EuK) pharmacophore (EuK-DOTA, EuK-107 and EuK-106, respectively) to enable targeting of PSMA. The metal ion selectivity for each construct was determined by incubation at 25 °C and 95 °C with the trivalent radiometals 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 +. PSMA binding affinity was determined by competitive binding using LNCaP cells, while in vivo tumor targeting of the 68Ga-labeled constructs was examined by positron emission tomography (PET) in LNCaP xenograft tumor-bearing mice. Results PMSA affinities (IC50 values) were 13.3 ± 0.9 nM for EuK-DOTA, 18.0 ± 3.7 nM for EuK-107 and 42.6 ± 6.6 nM for EuK-106. EuK-107 and EuK-DOTA proved to rapidly and near quantitatively complex 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 + at 95 °C, with EuK-107 also rapidly complexing 111In3 + and 177Lu3 + at 25 °C. The inability of EuK-106 to chelate 177Lu3 + and 225Ac3 + suggests that size of the cavity of the macrocylic ring may be more critical than the number of donor groups for the chelation of larger radiometals. In vivo, 68Ga-EuK-107 proved to have similar uptake to 68Ga-DKFZ-PSMA-617, a theranostic ligand currently in clinical evaluation, in a PSMA positive xenograft tumor model. Conclusions The broad metal ion selectivity, good in vitro affinity for PSMA and good in vivo tumor targeting suggest that EuK-107, with the 3p-C-DEPA chelator, merits further evaluation as a theranostics construct in prostate cancer.",
keywords = "3p-C-DEPA, Bifunctional chelate, PET, Prostate cancer, PSMA, Targeted radiotherapy",
author = "Kelly, {James M.} and Alejandro Amor-Coarasa and Anastasia Nikolopoulou and Dohyun Kim and Clarence Williams and Shankar Vallabhajosula and Babich, {John W.}",
year = "2017",
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language = "English (US)",
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pages = "38--46",
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TY - JOUR

T1 - Assessment of PSMA targeting ligands bearing novel chelates with application to theranostics

T2 - Stability and complexation kinetics of 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 +

AU - Kelly, James M.

AU - Amor-Coarasa, Alejandro

AU - Nikolopoulou, Anastasia

AU - Kim, Dohyun

AU - Williams, Clarence

AU - Vallabhajosula, Shankar

AU - Babich, John W.

PY - 2017/12

Y1 - 2017/12

N2 - Introduction Recent successes in the treatment of metastatic castration-resistant prostate cancer (mCRPCa) by systemic endoradiotherapy has sparked renewed interest in developing small molecule ligands targeting prostate-specific membrane antigen (PSMA) and chelators capable of stable complexation of metal radionuclides for imaging and therapy. As the size and coordination number of metals for imaging, such as 68Ga3 +, and for targeted therapy, such as 177Lu3 + and 225Ac3 +, are substantially different, they may show a preference for macrocycles of different denticity. We have prepared three simple conjugates that target PSMA and form radiometal complexes through coordination by either octa-, deca-, or dodecadentate tetraazacyclododecane chelators. The complex formation and metal ion selectivity of these constructs were determined at two relevant temperatures, complex stability was examined in vitro, and tumor targeting was demonstrated in preclinical PCa models with a view towards identifying a candidate with potential value as a theranostic agent for the imaging and therapy of mCRPCa. Methods Three bifunctional chelates with high denticity, including the octadentate chelate DOTA, the decadentate 3p-C-DEPA and a novel dodecadentate analogue of DEPA, were synthesized and conjugated to a glutamate-urea-lysine (EuK) pharmacophore (EuK-DOTA, EuK-107 and EuK-106, respectively) to enable targeting of PSMA. The metal ion selectivity for each construct was determined by incubation at 25 °C and 95 °C with the trivalent radiometals 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 +. PSMA binding affinity was determined by competitive binding using LNCaP cells, while in vivo tumor targeting of the 68Ga-labeled constructs was examined by positron emission tomography (PET) in LNCaP xenograft tumor-bearing mice. Results PMSA affinities (IC50 values) were 13.3 ± 0.9 nM for EuK-DOTA, 18.0 ± 3.7 nM for EuK-107 and 42.6 ± 6.6 nM for EuK-106. EuK-107 and EuK-DOTA proved to rapidly and near quantitatively complex 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 + at 95 °C, with EuK-107 also rapidly complexing 111In3 + and 177Lu3 + at 25 °C. The inability of EuK-106 to chelate 177Lu3 + and 225Ac3 + suggests that size of the cavity of the macrocylic ring may be more critical than the number of donor groups for the chelation of larger radiometals. In vivo, 68Ga-EuK-107 proved to have similar uptake to 68Ga-DKFZ-PSMA-617, a theranostic ligand currently in clinical evaluation, in a PSMA positive xenograft tumor model. Conclusions The broad metal ion selectivity, good in vitro affinity for PSMA and good in vivo tumor targeting suggest that EuK-107, with the 3p-C-DEPA chelator, merits further evaluation as a theranostics construct in prostate cancer.

AB - Introduction Recent successes in the treatment of metastatic castration-resistant prostate cancer (mCRPCa) by systemic endoradiotherapy has sparked renewed interest in developing small molecule ligands targeting prostate-specific membrane antigen (PSMA) and chelators capable of stable complexation of metal radionuclides for imaging and therapy. As the size and coordination number of metals for imaging, such as 68Ga3 +, and for targeted therapy, such as 177Lu3 + and 225Ac3 +, are substantially different, they may show a preference for macrocycles of different denticity. We have prepared three simple conjugates that target PSMA and form radiometal complexes through coordination by either octa-, deca-, or dodecadentate tetraazacyclododecane chelators. The complex formation and metal ion selectivity of these constructs were determined at two relevant temperatures, complex stability was examined in vitro, and tumor targeting was demonstrated in preclinical PCa models with a view towards identifying a candidate with potential value as a theranostic agent for the imaging and therapy of mCRPCa. Methods Three bifunctional chelates with high denticity, including the octadentate chelate DOTA, the decadentate 3p-C-DEPA and a novel dodecadentate analogue of DEPA, were synthesized and conjugated to a glutamate-urea-lysine (EuK) pharmacophore (EuK-DOTA, EuK-107 and EuK-106, respectively) to enable targeting of PSMA. The metal ion selectivity for each construct was determined by incubation at 25 °C and 95 °C with the trivalent radiometals 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 +. PSMA binding affinity was determined by competitive binding using LNCaP cells, while in vivo tumor targeting of the 68Ga-labeled constructs was examined by positron emission tomography (PET) in LNCaP xenograft tumor-bearing mice. Results PMSA affinities (IC50 values) were 13.3 ± 0.9 nM for EuK-DOTA, 18.0 ± 3.7 nM for EuK-107 and 42.6 ± 6.6 nM for EuK-106. EuK-107 and EuK-DOTA proved to rapidly and near quantitatively complex 68Ga3 +, 111In3 +, 177Lu3 + and 225Ac3 + at 95 °C, with EuK-107 also rapidly complexing 111In3 + and 177Lu3 + at 25 °C. The inability of EuK-106 to chelate 177Lu3 + and 225Ac3 + suggests that size of the cavity of the macrocylic ring may be more critical than the number of donor groups for the chelation of larger radiometals. In vivo, 68Ga-EuK-107 proved to have similar uptake to 68Ga-DKFZ-PSMA-617, a theranostic ligand currently in clinical evaluation, in a PSMA positive xenograft tumor model. Conclusions The broad metal ion selectivity, good in vitro affinity for PSMA and good in vivo tumor targeting suggest that EuK-107, with the 3p-C-DEPA chelator, merits further evaluation as a theranostics construct in prostate cancer.

KW - 3p-C-DEPA

KW - Bifunctional chelate

KW - PET

KW - Prostate cancer

KW - PSMA

KW - Targeted radiotherapy

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