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. 2016 Feb 17;27(2):309-18.
doi: 10.1021/acs.bioconjchem.5b00335. Epub 2015 Sep 2.

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

Michelle T Ma  1 , Carleen Cullinane  2   3 , Cinzia Imberti  1 , Julia Baguña Torres  1 , Samantha Y A Terry  1 , Peter Roselt  2 , Rodney J Hicks  2   3 , Philip J Blower  1
Affiliations

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

Michelle T Ma et al. Bioconjug Chem. .

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.

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Conflict of interest statement

The authors declare the following competing financial interest(s): PJB holds patents whose claims encompass the newly described chelators. All other authors declare that they have no conflict of interest.

Figures

Chart 1
Chart 1. Structures of H3THP-Ac and H3-THP-mal
Scheme 1
Scheme 1. Synthesis of Tris(hydroxpyridinone) Bifunctional Chelators Containing Isothiocyanate Groups, H3THP-NCS (top) and H3THP-PhNCS (bottom)
Figure 1
Figure 1
(a) H3THP-NCS-RGD; (b) HPLC traces (λ220) of H3THP-NCS-RGD (black) and [natGa(THP-NCS-RGD)] (blue), and radio-HPLC trace of [68Ga(THP-NCS-RGD)] (red). Inset: Mass spectral signal of [natGa(THP-NCS-RGD) + 2H]2+; (c) H3THP-PhNCS-RGD; (d) HPLC traces (λ220) of H3THP-PhNCS-RGD (black) and [natGa(THP-PhNCS-RGD)] (blue), and radio-HPLC trace of [68Ga(THP-PhNCS-RGD)] (red). Inset: Mass spectral signal of [natGa(THP-PhNCS-RGD) + 2H]2+.
Figure 2
Figure 2
Mean concentration response curve for 125I-echistatin titrated with [Ga(THP-NCS-RGD)] (black), [Ga(THP-PhNCS-RGD)] (red), and RGD (blue) (n = 6 for each concentration; error bars correspond to standard error of the mean).
Figure 3
Figure 3
PET imaging and ex vivo biodistribution of (a) [68Ga(THP-NCS-RGD)] and (b) [68Ga(THP-PhNCS-RGD)]. Representative PET maximum intensity projection of Balb/c nu/nu mice bearing a U87MG tumor on right flank at (i) 1 h PI of tracer, (ii) 1 h after coinjection of tracer and RGD, and (iii) 2 h PI of tracer, (iv) ex vivo biodistribution in mice at 1 and 2 h PI of tracer, and 1 h PI of tracer coadministered with RGD (blocked); n = 3. Error bars correspond to standard error of the mean.
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