Investigation of imaging the somatostatin receptor by opening the blood-brain barrier with melittin – A feasibility study using positron emission tomography and [64Cu]Cu-DOTATATE

DOTATATE is a somatostatin peptide analog used in the clinic to detect somatostatin receptors which are highly expressed on neuroendocrine tumors. Somatostatin receptors are found naturally in the intestines, pancreas, lungs, and brain (mainly cortex). In vivo measurement of the somatostatin recepto...

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Published inNuclear medicine and biology Vol. 132-133; p. 108905
Main Authors Andersen, Ida Vang, Bidesi, Natasha Shalina Rajani, Shalgunov, Vladimir, Jørgensen, Jesper Tranekjær, Gustavsson, Tobias, Strømgaard, Kristian, Ingemann Jensen, Andreas T., Kjær, Andreas, Herth, Matthias M.
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LanguageEnglish
Published United States Elsevier Inc 01.05.2024
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Abstract DOTATATE is a somatostatin peptide analog used in the clinic to detect somatostatin receptors which are highly expressed on neuroendocrine tumors. Somatostatin receptors are found naturally in the intestines, pancreas, lungs, and brain (mainly cortex). In vivo measurement of the somatostatin receptors in the cortex has been challenging because available tracers cannot cross the blood-brain barrier (BBB) due to their intrinsic polarity. A peptide called melittin, a main component of honeybee venom, has been shown to disrupt plasma membranes and increase the permeability of biological membranes. In this study, we assessed the feasibility of using melittin to facilitate the passage of [64Cu]Cu-DOTATATE through the BBB and its binding to somatostatin receptors in the cortex. Evaluation included in vitro autoradiography on Long Evans rat brains to estimate the binding affinity of [64Cu]Cu-DOTATATE to the somatostatin receptors in the cortex and an in vivo evaluation of [64Cu]Cu-DOTATATE binding in NMRI mice after injection of melittin. This study found an in vitro Bmax = 89 ± 4 nM and KD = 4.5 ± 0.6 nM in the cortex, resulting in a theoretical binding potential (BP) calculated as Bmax/KD ≈ 20, which is believed suitable for in vivo brain PET imaging. However, the in vivo results showed no significant difference between the control and melittin injected mice, indicating that the honeybee venom failed to open the BBB. Additional experiments, potentially involving faster injection rates are required to verify that melittin can increase brain uptake of non-BBB permeable PET tracers. Furthermore, an evaluation of whether a venom with a narrow therapeutic range can be used for clinical purposes needs to be considered. [Display omitted]
AbstractList DOTATATE is a somatostatin peptide analog used in the clinic to detect somatostatin receptors which are highly expressed on neuroendocrine tumors. Somatostatin receptors are found naturally in the intestines, pancreas, lungs, and brain (mainly cortex). In vivo measurement of the somatostatin receptors in the cortex has been challenging because available tracers cannot cross the blood-brain barrier (BBB) due to their intrinsic polarity. A peptide called melittin, a main component of honeybee venom, has been shown to disrupt plasma membranes and increase the permeability of biological membranes. In this study, we assessed the feasibility of using melittin to facilitate the passage of [64Cu]Cu-DOTATATE through the BBB and its binding to somatostatin receptors in the cortex. Evaluation included in vitro autoradiography on Long Evans rat brains to estimate the binding affinity of [64Cu]Cu-DOTATATE to the somatostatin receptors in the cortex and an in vivo evaluation of [64Cu]Cu-DOTATATE binding in NMRI mice after injection of melittin. This study found an in vitro Bmax = 89 ± 4 nM and KD = 4.5 ± 0.6 nM in the cortex, resulting in a theoretical binding potential (BP) calculated as Bmax/KD ≈ 20, which is believed suitable for in vivo brain PET imaging. However, the in vivo results showed no significant difference between the control and melittin injected mice, indicating that the honeybee venom failed to open the BBB. Additional experiments, potentially involving faster injection rates are required to verify that melittin can increase brain uptake of non-BBB permeable PET tracers. Furthermore, an evaluation of whether a venom with a narrow therapeutic range can be used for clinical purposes needs to be considered. [Display omitted]
DOTATATE is a somatostatin peptide analog used in the clinic to detect somatostatin receptors which are highly expressed on neuroendocrine tumors. Somatostatin receptors are found naturally in the intestines, pancreas, lungs, and brain (mainly cortex). In vivo measurement of the somatostatin receptors in the cortex has been challenging because available tracers cannot cross the blood-brain barrier (BBB) due to their intrinsic polarity. A peptide called melittin, a main component of honeybee venom, has been shown to disrupt plasma membranes and increase the permeability of biological membranes. In this study, we assessed the feasibility of using melittin to facilitate the passage of [ Cu]Cu-DOTATATE through the BBB and its binding to somatostatin receptors in the cortex. Evaluation included in vitro autoradiography on Long Evans rat brains to estimate the binding affinity of [ Cu]Cu-DOTATATE to the somatostatin receptors in the cortex and an in vivo evaluation of [ Cu]Cu-DOTATATE binding in NMRI mice after injection of melittin. This study found an in vitro B  = 89 ± 4 nM and K  = 4.5 ± 0.6 nM in the cortex, resulting in a theoretical binding potential (BP) calculated as B /K  ≈ 20, which is believed suitable for in vivo brain PET imaging. However, the in vivo results showed no significant difference between the control and melittin injected mice, indicating that the honeybee venom failed to open the BBB. Additional experiments, potentially involving faster injection rates are required to verify that melittin can increase brain uptake of non-BBB permeable PET tracers. Furthermore, an evaluation of whether a venom with a narrow therapeutic range can be used for clinical purposes needs to be considered.
ArticleNumber 108905
Author Jørgensen, Jesper Tranekjær
Strømgaard, Kristian
Gustavsson, Tobias
Herth, Matthias M.
Shalgunov, Vladimir
Bidesi, Natasha Shalina Rajani
Ingemann Jensen, Andreas T.
Kjær, Andreas
Andersen, Ida Vang
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  surname: Andersen
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  givenname: Natasha Shalina Rajani
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  givenname: Vladimir
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  fullname: Shalgunov, Vladimir
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  givenname: Jesper Tranekjær
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  givenname: Andreas T.
  surname: Ingemann Jensen
  fullname: Ingemann Jensen, Andreas T.
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  givenname: Andreas
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  givenname: Matthias M.
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  email: matthias.herth@sund.ku.dk
  organization: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, Denmark
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Keywords Autoradiography
Melittin
BBB
Blood-brain barrier
DOTATATE
SSTR
64Cu
Somatostatin
Biodistribution
PET
Cu
Language English
License This is an open access article under the CC BY license.
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Snippet DOTATATE is a somatostatin peptide analog used in the clinic to detect somatostatin receptors which are highly expressed on neuroendocrine tumors. Somatostatin...
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pubmed
elsevier
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StartPage 108905
SubjectTerms 64Cu
Autoradiography
BBB
Biodistribution
Blood-brain barrier
DOTATATE
Melittin
PET
Somatostatin
SSTR
Title Investigation of imaging the somatostatin receptor by opening the blood-brain barrier with melittin – A feasibility study using positron emission tomography and [64Cu]Cu-DOTATATE
URI https://dx.doi.org/10.1016/j.nucmedbio.2024.108905
https://www.ncbi.nlm.nih.gov/pubmed/38555651
Volume 132-133
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