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New Tris(hydroxypyridinone) Bifunctional Chelators Containing Isothiocyanate Groups Provide a Versatile Platform for Rapid One-Step Labeling and PET Imaging with (68)Ga(3.).

Ma MT, Cullinane C, Imberti C, Baguña Torres J, Terry SY, Roselt P, Hicks RJ, Blower PJ - Bioconjug. Chem. (2015)

Bottom Line: Both compounds have been conjugated with the primary amine group of a cyclic integrin targeting peptide, RGD.Each conjugate can be radiolabeled and formulated by treatment with generator-produced (68)Ga(3+) in over 95% radiochemical yield under ambient conditions in less than 5 min, with specific activities of 60-80 MBq nmol(-1).We conclude that bifunctional THP chelators can be used for simple, efficient labeling of (68)Ga biomolecules under mild conditions suitable for peptides and proteins.

View Article: PubMed Central - PubMed

Affiliation: King's College London , Division of Imaging Sciences and Biomedical Engineering, Fourth Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, United Kingdom.

ABSTRACT
Two new bifunctional tris(hydroxypyridinone) (THP) chelators designed specifically for rapid labeling with (68)Ga have been synthesized, each with pendant isothiocyanate groups and three 1,6-dimethyl-3-hydroxypyridin-4-one groups. Both compounds have been conjugated with the primary amine group of a cyclic integrin targeting peptide, RGD. Each conjugate can be radiolabeled and formulated by treatment with generator-produced (68)Ga(3+) in over 95% radiochemical yield under ambient conditions in less than 5 min, with specific activities of 60-80 MBq nmol(-1). Competitive binding assays and in vivo biodistribution in mice bearing U87MG tumors demonstrate that the new (68)Ga(3+)-labeled THP peptide conjugates retain affinity for the αvβ3 integrin receptor, clear within 1-2 h from circulation, and undergo receptor-mediated tumor uptake in vivo. We conclude that bifunctional THP chelators can be used for simple, efficient labeling of (68)Ga biomolecules under mild conditions suitable for peptides and proteins.

No MeSH data available.


Related in: MedlinePlus

PET imagingand ex vivo biodistribution of (a) [68Ga(THP-NCS-RGD)]and (b) [68Ga(THP-PhNCS-RGD)]. Representative PET maximumintensity projection of Balb/c nu/nu mice bearing a U87MG tumor onright flank at (i) 1 h PI of tracer, (ii) 1 h after coinjection oftracer and RGD, and (iii) 2 h PI of tracer, (iv) ex vivo biodistributionin mice at 1 and 2 h PI of tracer, and 1 h PI of tracer coadministeredwith RGD (blocked); n = 3. Error bars correspondto standard error of the mean.
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fig3: PET imagingand ex vivo biodistribution of (a) [68Ga(THP-NCS-RGD)]and (b) [68Ga(THP-PhNCS-RGD)]. Representative PET maximumintensity projection of Balb/c nu/nu mice bearing a U87MG tumor onright flank at (i) 1 h PI of tracer, (ii) 1 h after coinjection oftracer and RGD, and (iii) 2 h PI of tracer, (iv) ex vivo biodistributionin mice at 1 and 2 h PI of tracer, and 1 h PI of tracer coadministeredwith RGD (blocked); n = 3. Error bars correspondto standard error of the mean.

Mentions: In PET scans of mice administered[68Ga(THP-NCS-RGD)] 1 h PI (Figure 3a), the tumor was visible, with a tumor tobackground (mediastinum) concentration ratio of 2.76 ± 0.18.The kidneys and liver of all animals were also discernible with atumor to kidney concentration ratio of 1.03 ± 0.05, and a tumorto liver concentration ratio of 1.59 ± 0.16. There was no evidenceof bone uptake being above that of surrounding muscle. Excretion waslargely renal and the bladder was associated with the highest levelsof activity in all PET images. Images of animals coadministered RGDdemonstrated that RGD effectively blocks αvβ3 integrin receptor binding by [68Ga(THP-NCS-RGD)].


New Tris(hydroxypyridinone) Bifunctional Chelators Containing Isothiocyanate Groups Provide a Versatile Platform for Rapid One-Step Labeling and PET Imaging with (68)Ga(3.).

Ma MT, Cullinane C, Imberti C, Baguña Torres J, Terry SY, Roselt P, Hicks RJ, Blower PJ - Bioconjug. Chem. (2015)

PET imagingand ex vivo biodistribution of (a) [68Ga(THP-NCS-RGD)]and (b) [68Ga(THP-PhNCS-RGD)]. Representative PET maximumintensity projection of Balb/c nu/nu mice bearing a U87MG tumor onright flank at (i) 1 h PI of tracer, (ii) 1 h after coinjection oftracer and RGD, and (iii) 2 h PI of tracer, (iv) ex vivo biodistributionin mice at 1 and 2 h PI of tracer, and 1 h PI of tracer coadministeredwith RGD (blocked); n = 3. Error bars correspondto standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4759618&req=5

fig3: PET imagingand ex vivo biodistribution of (a) [68Ga(THP-NCS-RGD)]and (b) [68Ga(THP-PhNCS-RGD)]. Representative PET maximumintensity projection of Balb/c nu/nu mice bearing a U87MG tumor onright flank at (i) 1 h PI of tracer, (ii) 1 h after coinjection oftracer and RGD, and (iii) 2 h PI of tracer, (iv) ex vivo biodistributionin mice at 1 and 2 h PI of tracer, and 1 h PI of tracer coadministeredwith RGD (blocked); n = 3. Error bars correspondto standard error of the mean.
Mentions: In PET scans of mice administered[68Ga(THP-NCS-RGD)] 1 h PI (Figure 3a), the tumor was visible, with a tumor tobackground (mediastinum) concentration ratio of 2.76 ± 0.18.The kidneys and liver of all animals were also discernible with atumor to kidney concentration ratio of 1.03 ± 0.05, and a tumorto liver concentration ratio of 1.59 ± 0.16. There was no evidenceof bone uptake being above that of surrounding muscle. Excretion waslargely renal and the bladder was associated with the highest levelsof activity in all PET images. Images of animals coadministered RGDdemonstrated that RGD effectively blocks αvβ3 integrin receptor binding by [68Ga(THP-NCS-RGD)].

Bottom Line: Both compounds have been conjugated with the primary amine group of a cyclic integrin targeting peptide, RGD.Each conjugate can be radiolabeled and formulated by treatment with generator-produced (68)Ga(3+) in over 95% radiochemical yield under ambient conditions in less than 5 min, with specific activities of 60-80 MBq nmol(-1).We conclude that bifunctional THP chelators can be used for simple, efficient labeling of (68)Ga biomolecules under mild conditions suitable for peptides and proteins.

View Article: PubMed Central - PubMed

Affiliation: King's College London , Division of Imaging Sciences and Biomedical Engineering, Fourth Floor Lambeth Wing, St Thomas' Hospital, London SE1 7EH, United Kingdom.

ABSTRACT
Two new bifunctional tris(hydroxypyridinone) (THP) chelators designed specifically for rapid labeling with (68)Ga have been synthesized, each with pendant isothiocyanate groups and three 1,6-dimethyl-3-hydroxypyridin-4-one groups. Both compounds have been conjugated with the primary amine group of a cyclic integrin targeting peptide, RGD. Each conjugate can be radiolabeled and formulated by treatment with generator-produced (68)Ga(3+) in over 95% radiochemical yield under ambient conditions in less than 5 min, with specific activities of 60-80 MBq nmol(-1). Competitive binding assays and in vivo biodistribution in mice bearing U87MG tumors demonstrate that the new (68)Ga(3+)-labeled THP peptide conjugates retain affinity for the αvβ3 integrin receptor, clear within 1-2 h from circulation, and undergo receptor-mediated tumor uptake in vivo. We conclude that bifunctional THP chelators can be used for simple, efficient labeling of (68)Ga biomolecules under mild conditions suitable for peptides and proteins.

No MeSH data available.


Related in: MedlinePlus