Ballinger, J. R.

Blower, P. J.

Cooper, M. S.

Cullinane, C.

Hicks, R. J.

Imberti, C.

Ma, M. T.

Meszaros, L.

Mullen, G. E. D.

Paterson, B.

Roselt, P.

Terry, S. Y. A.

Young, J. D.

The gallium-68 (68Ga) generator offers PET molecular imaging to hospitals without a cyclotron if simple labelling methods are devised. Current 68Ga clinical radiopharmaceutical syntheses require high temperatures (greater than 90 ?C), and extended reaction times (5 - 20 min). We have previously shown that tris(hydroxypyridinone) (THP) ligands rapidly label with 68Ga quantitatively under mild conditions (Chem Commun, 2011; 47:7068). We now report the development of one-step labelling methods equivalent to kit formulation protocols, and the ability of 68Ga-THP peptide conjugates to image expression of peptide receptors in tumours in vivo. The THP-Ac chelator was labelled with 68Ga-generator eluate under a range of THP-Ac concentrations (0.1-1000 μ M), pH values (4 - 7), buffers, and trace metal concentrations (Mg(II), Fe(III), Zn(II)). At 10 μ M, 20 ?C and all pH values and times, labelling efficiency of THP-Ac reached greater than 95% in under 2 min, and was unaffected by contaminating Mg(II), Zn(II) and Fe(III) at 30, 20, 0.3 mg/L, respectively. Vials containing lyophilised THP-Ac and buffer salts gave quantitative radiolabelling with unprocessed eluate in less than 5 min. New bifunctional chelator isothiocyanate and carboxylate derivatives of THP were synthesised and conjugated to (i) cyclic(RGDfK) peptides for targeting α v β 3 integrin expression, (ii) Tyr3-octreotate (TATE) peptide for targeting SSTR2 expression in neuroendocrine tumours, (iii) a urea-containing peptide targeting PSMA receptors for prostate tumours, and (iv) the monoclonal antibody, trastuzumab for HER2 receptors. All conjugates were labelled with 68Ga in greater than 95% radiochemical yield and high specific activity (up to 80 MBq/nmol at the point of administration) at 25 ?C and formulated to pH 6 - 7 in 2 - 5 min. Biodistribution of tested αvβ3- and SSTR-targeting conjugates showed tumour-specific uptake and retention of target receptor affinity. Excretion was rapid and predominantly renal. Serum stability and biodistribution experiments point to excellent in vivo stability of the new radiotracers with respect to the 68Ga-THP complex. Notably, in vivo tumour uptake and biodistribution of 68Ga-THP-TATE was comparable to that of the clinical radiopharmaceutical, 68Ga-DOTA-TATE.The new tris(hydroxypyridinone) chelator and its conjugates enable rapid radiolabelling with 68Ga under mild conditions without subsequent purification. The simplicity of radiochemical syntheses based on such conjugates is conducive to translation to one-step kit-based radiosyntheses that would greatly facilitate the expansion and adoption of 68Ga PET in hospitals

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Extremely rapid, kit-based biomolecule labelling and molecular imaging with gallium-68:tris(hydroxypyridinone) chelators

Extremely rapid, kit-based biomolecule labelling and molecular imaging with gallium-68:tris(hydroxypyridinone) chelators

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