Development of Radiopharmaceuticals for NPY Receptor-5 (Y5) Nuclear Imaging in Tumors by Synthesis of Specific Agonists and Investigation of Their Binding Mode
The neuropeptide-Y (NPY) family acts through four G protein-coupled receptor subtypes in humans, namely, Y , Y , Y , and Y . A growing body of evidence suggest the involvement of the NPY system in several cancers, notably the Y subtype, thus acting as a relevant target for the development of radioph...
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| Vydáno v: | Bioconjugate chemistry Ročník 34; číslo 11; s. 2014 |
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| Hlavní autoři: | , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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15.11.2023
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| ISSN: | 1520-4812, 1520-4812 |
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| Abstract | The neuropeptide-Y (NPY) family acts through four G protein-coupled receptor subtypes in humans, namely, Y
, Y
, Y
, and Y
. A growing body of evidence suggest the involvement of the NPY system in several cancers, notably the Y
subtype, thus acting as a relevant target for the development of radiopharmaceuticals for imaging or targeted radionuclide therapy (TRT). Here, the [cPP(1-7),NPY(19-23),Ala
,Aib
,Gln
]hPP scaffold, further referred to as sY
ago, was modified with a DOTA chelator and radiolabeled with
Ga and
In and investigated
and
using the MCF-7 model. For
studies, MCF-7 cells were orthotopically implanted in female nude mice and imaging with small animal positron emission tomography/computed tomography (μPET/CT) was performed. At the end of imaging, the mice were sacrificed. A scrambled version of sY
ago, which was also modified with a DOTA chelator, served as a negative control (DOTA-[Nle]sY
ago_scrambled). sY
ago and DOTA-sY
ago showed subnanomolar affinity toward the Y
(0.9 ± 0.1 and 0.8 ± 0.1 nM, respectively) and a single binding site at the Y
was identified. [
Ga]Ga-DOTA-sY
ago and [
In]In-DOTA-sY
ago were hydrophilic and showed high specific internalization (1.61 ± 0.75%/10
cells at 1 h) and moderate efflux (55% of total binding externalized at 45 min). On μPET/CT images, most of the signal was depicted in the kidneys and the liver. MCF-7 tumors were clearly visualized. On biodistribution studies, [
Ga]Ga-DOTA-sY
ago was eliminated by the kidneys (∼60 %ID/g). The kidney uptake is Y
-mediated. A specific uptake was also noted in the liver (5.09 ± 1.15 %ID/g vs 1.13 ± 0.21 %ID/g for [
Ga]Ga-DOTA-[Nle]sY
ago_scrambled,
< 0.05), the lungs (1.03 ± 0.34 %ID/g vs 0.20 %ID/g,
< 0.05), and the spleen (0.85 ± 0.09%ID/g vs 0.16 ± 0.16%ID/g,
< 0.05). In MCF-7 tumors, [
Ga]Ga-DOTA-sY
ago showed 12-fold higher uptake than [
Ga]Ga-DOTA-[Nle]sY
ago_scrambled (3.43 ± 2.32 vs 0.27 ± 0.15 %ID/g, respectively,
= 0.0008) at 1 h post-injection. Finally, a proof-of-principle tissular micro-imaging study on a human primary cancer sample showed weak binding of [
In]In-DOTA-sY
ago in prostatic intra-neoplasia and high binding in the ISUP1 lesion while normal prostate was free of signal. |
|---|---|
| AbstractList | The neuropeptide-Y (NPY) family acts through four G protein-coupled receptor subtypes in humans, namely, Y
, Y
, Y
, and Y
. A growing body of evidence suggest the involvement of the NPY system in several cancers, notably the Y
subtype, thus acting as a relevant target for the development of radiopharmaceuticals for imaging or targeted radionuclide therapy (TRT). Here, the [cPP(1-7),NPY(19-23),Ala
,Aib
,Gln
]hPP scaffold, further referred to as sY
ago, was modified with a DOTA chelator and radiolabeled with
Ga and
In and investigated
and
using the MCF-7 model. For
studies, MCF-7 cells were orthotopically implanted in female nude mice and imaging with small animal positron emission tomography/computed tomography (μPET/CT) was performed. At the end of imaging, the mice were sacrificed. A scrambled version of sY
ago, which was also modified with a DOTA chelator, served as a negative control (DOTA-[Nle]sY
ago_scrambled). sY
ago and DOTA-sY
ago showed subnanomolar affinity toward the Y
(0.9 ± 0.1 and 0.8 ± 0.1 nM, respectively) and a single binding site at the Y
was identified. [
Ga]Ga-DOTA-sY
ago and [
In]In-DOTA-sY
ago were hydrophilic and showed high specific internalization (1.61 ± 0.75%/10
cells at 1 h) and moderate efflux (55% of total binding externalized at 45 min). On μPET/CT images, most of the signal was depicted in the kidneys and the liver. MCF-7 tumors were clearly visualized. On biodistribution studies, [
Ga]Ga-DOTA-sY
ago was eliminated by the kidneys (∼60 %ID/g). The kidney uptake is Y
-mediated. A specific uptake was also noted in the liver (5.09 ± 1.15 %ID/g vs 1.13 ± 0.21 %ID/g for [
Ga]Ga-DOTA-[Nle]sY
ago_scrambled,
< 0.05), the lungs (1.03 ± 0.34 %ID/g vs 0.20 %ID/g,
< 0.05), and the spleen (0.85 ± 0.09%ID/g vs 0.16 ± 0.16%ID/g,
< 0.05). In MCF-7 tumors, [
Ga]Ga-DOTA-sY
ago showed 12-fold higher uptake than [
Ga]Ga-DOTA-[Nle]sY
ago_scrambled (3.43 ± 2.32 vs 0.27 ± 0.15 %ID/g, respectively,
= 0.0008) at 1 h post-injection. Finally, a proof-of-principle tissular micro-imaging study on a human primary cancer sample showed weak binding of [
In]In-DOTA-sY
ago in prostatic intra-neoplasia and high binding in the ISUP1 lesion while normal prostate was free of signal. The neuropeptide-Y (NPY) family acts through four G protein-coupled receptor subtypes in humans, namely, Y1, Y2, Y4, and Y5. A growing body of evidence suggest the involvement of the NPY system in several cancers, notably the Y5 subtype, thus acting as a relevant target for the development of radiopharmaceuticals for imaging or targeted radionuclide therapy (TRT). Here, the [cPP(1-7),NPY(19-23),Ala31,Aib32,Gln34]hPP scaffold, further referred to as sY5ago, was modified with a DOTA chelator and radiolabeled with 68Ga and 111In and investigated in vitro and in vivo using the MCF-7 model. For in vivo studies, MCF-7 cells were orthotopically implanted in female nude mice and imaging with small animal positron emission tomography/computed tomography (μPET/CT) was performed. At the end of imaging, the mice were sacrificed. A scrambled version of sY5ago, which was also modified with a DOTA chelator, served as a negative control (DOTA-[Nle]sY5ago_scrambled). sY5ago and DOTA-sY5ago showed subnanomolar affinity toward the Y5 (0.9 ± 0.1 and 0.8 ± 0.1 nM, respectively) and a single binding site at the Y5 was identified. [68Ga]Ga-DOTA-sY5ago and [111In]In-DOTA-sY5ago were hydrophilic and showed high specific internalization (1.61 ± 0.75%/106 cells at 1 h) and moderate efflux (55% of total binding externalized at 45 min). On μPET/CT images, most of the signal was depicted in the kidneys and the liver. MCF-7 tumors were clearly visualized. On biodistribution studies, [68Ga]Ga-DOTA-sY5ago was eliminated by the kidneys (∼60 %ID/g). The kidney uptake is Y5-mediated. A specific uptake was also noted in the liver (5.09 ± 1.15 %ID/g vs 1.13 ± 0.21 %ID/g for [68Ga]Ga-DOTA-[Nle]sY5ago_scrambled, p < 0.05), the lungs (1.03 ± 0.34 %ID/g vs 0.20 %ID/g, p < 0.05), and the spleen (0.85 ± 0.09%ID/g vs 0.16 ± 0.16%ID/g, p < 0.05). In MCF-7 tumors, [68Ga]Ga-DOTA-sY5ago showed 12-fold higher uptake than [68Ga]Ga-DOTA-[Nle]sY5ago_scrambled (3.43 ± 2.32 vs 0.27 ± 0.15 %ID/g, respectively, p = 0.0008) at 1 h post-injection. Finally, a proof-of-principle tissular micro-imaging study on a human primary cancer sample showed weak binding of [111In]In-DOTA-sY5ago in prostatic intra-neoplasia and high binding in the ISUP1 lesion while normal prostate was free of signal.The neuropeptide-Y (NPY) family acts through four G protein-coupled receptor subtypes in humans, namely, Y1, Y2, Y4, and Y5. A growing body of evidence suggest the involvement of the NPY system in several cancers, notably the Y5 subtype, thus acting as a relevant target for the development of radiopharmaceuticals for imaging or targeted radionuclide therapy (TRT). Here, the [cPP(1-7),NPY(19-23),Ala31,Aib32,Gln34]hPP scaffold, further referred to as sY5ago, was modified with a DOTA chelator and radiolabeled with 68Ga and 111In and investigated in vitro and in vivo using the MCF-7 model. For in vivo studies, MCF-7 cells were orthotopically implanted in female nude mice and imaging with small animal positron emission tomography/computed tomography (μPET/CT) was performed. At the end of imaging, the mice were sacrificed. A scrambled version of sY5ago, which was also modified with a DOTA chelator, served as a negative control (DOTA-[Nle]sY5ago_scrambled). sY5ago and DOTA-sY5ago showed subnanomolar affinity toward the Y5 (0.9 ± 0.1 and 0.8 ± 0.1 nM, respectively) and a single binding site at the Y5 was identified. [68Ga]Ga-DOTA-sY5ago and [111In]In-DOTA-sY5ago were hydrophilic and showed high specific internalization (1.61 ± 0.75%/106 cells at 1 h) and moderate efflux (55% of total binding externalized at 45 min). On μPET/CT images, most of the signal was depicted in the kidneys and the liver. MCF-7 tumors were clearly visualized. On biodistribution studies, [68Ga]Ga-DOTA-sY5ago was eliminated by the kidneys (∼60 %ID/g). The kidney uptake is Y5-mediated. A specific uptake was also noted in the liver (5.09 ± 1.15 %ID/g vs 1.13 ± 0.21 %ID/g for [68Ga]Ga-DOTA-[Nle]sY5ago_scrambled, p < 0.05), the lungs (1.03 ± 0.34 %ID/g vs 0.20 %ID/g, p < 0.05), and the spleen (0.85 ± 0.09%ID/g vs 0.16 ± 0.16%ID/g, p < 0.05). In MCF-7 tumors, [68Ga]Ga-DOTA-sY5ago showed 12-fold higher uptake than [68Ga]Ga-DOTA-[Nle]sY5ago_scrambled (3.43 ± 2.32 vs 0.27 ± 0.15 %ID/g, respectively, p = 0.0008) at 1 h post-injection. Finally, a proof-of-principle tissular micro-imaging study on a human primary cancer sample showed weak binding of [111In]In-DOTA-sY5ago in prostatic intra-neoplasia and high binding in the ISUP1 lesion while normal prostate was free of signal. |
| Author | Vimont, Delphine Hindié, Elif Morgat, Clément Schollhammer, Romain Beck-Sickinger, Annette G Alves, Isabel D Ait-Arsa, Imade Velasco, Valérie Peuker, Lisa C Bodin, Sacha MacGrogan, Gaétan Lamare, Frédéric Jestin, Emmanuelle |
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| Snippet | The neuropeptide-Y (NPY) family acts through four G protein-coupled receptor subtypes in humans, namely, Y
, Y
, Y
, and Y
. A growing body of evidence suggest... The neuropeptide-Y (NPY) family acts through four G protein-coupled receptor subtypes in humans, namely, Y1, Y2, Y4, and Y5. A growing body of evidence suggest... |
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| StartPage | 2014 |
| Title | Development of Radiopharmaceuticals for NPY Receptor-5 (Y5) Nuclear Imaging in Tumors by Synthesis of Specific Agonists and Investigation of Their Binding Mode |
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