Hydroxypyridinone Chelators: From Iron Scavenging to Radiopharmaceuticals for PET Imaging with Gallium-68

Abstract

Derivatives of 3,4-hydroxypyridinones have been extensively studied for in vivo Fe3+ sequestration. Deferiprone, a 1,2-dimethyl-3,4-hydroxypyridinone, is now routinely used for clinical treatment of iron overload disease. Hexadentate tris(3,4-hydroxypyridinone) ligands (THP) complex Fe3+ at very low iron concentrations, and their high affinities for oxophilic trivalent metal ions have led to their development for new applications as bifunctional chelators for the positron emitting radiometal, 68Ga3+, which is clinically used for molecular imaging in positron emission tomography (PET). THP-peptide bioconjugates rapidly and quantitatively complex 68Ga3+ at ambient temperature, neutral pH and micromolar concentrations of ligand, making them amenable to kit-based radiosynthesis of 68Ga PET radiopharmaceuticals. 68Ga-labelled THP-peptides accumulate at target tissue in vivo, and are excreted largely via a renal pathway, providing high quality PET images.

The effects of trace metal impurities on Ga-68-radiolabelling with a tris(3-hydroxy-1,6-dimethylpyridin-4-one) (THP) chelator

“…THP ligands were originally developed as iron-sequestering chelators, 25,26 and so as well as having high affinity for Ga 3+ , THP also has high affinity for Fe 3+ , Al 3+ and other oxiphilic transition metal ions. 12,13,[27][28][29] The highest molar activity that we have achieved for a THP conjugate to date is 80 MBq nmol À1 , 11,19 equating to <0.1% 68 Ga 3+ occupancy of THP in these solutions. This is comparatively low compared to other radiometallated conjugatesfor example, some DTPA-or DOTA-conjugates with 111 In can achieve specic activities up to 1 GBq nmol À1 , 30 and TRAP-conjugates with 68 Ga can achieve over 4.8 GBq nmol À1 , although the latter is obtained under reaction conditions that result in <70% RCY.…”

“…1) that rapidly and quantitatively incorporates 68 Ga 3+ at room temperature, neutral pH, and low chelator concentrations, giving a single species. [11][12][13] It is consequently well-suited to kit-based 68 Garadiopharmceutical synthesis, unlike other common gallium chelators such as DOTA and HBED-CC. THP has demonstrated superior radiolabelling properties compared to many other chelators, with higher RCYs achievable for THP at very low concentration compared to e.g.…”

Manipulating the In Vivo Behaviour of 68Ga with Tris(Hydroxypyridinone) Chelators: Pretargeting and Blood Clearance

“…Thus, 68 Ga 3+ and THP Me (or THP H ) represent a potential chemical pretargeting pair. Notably, several BFC have been developed based on THP Me , including isothiocyanate (THP Me -NCS, Figure 1A) and maleimide derivatives that can effectively bind to lysine or cysteine side chains, respectively, in mild conditions (aqueous solution, mildly basic pH, room temperature), allowing facile conjugation to antibodies [10,13,14].…”

In silico design of mimosine containing peptides as new efficient chelators of aluminum

“…11 DFP was extensively studied during past years by Hider [12][13][14] and Santos, [15][16][17] who prepared its oligodentate derivatives mostly as Fe(III) chelators, which ultimately found new application as Ga 68 complexes for PET immagining. 14,18,19 Recently, Abbate et al reported novel targeting peptides incorporating DFP as the iron(III) chelating units. 20 Nevertheless, there is an urgent need for other, more efficient, less toxic and cheaper aluminum chelators.…”