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Tuning the properties of tris(hydroxypyridinone) ligands: efficient Ga-68 chelators for PET imaging: efficient 68Ga chelators for PET imaging

Research output: Contribution to journalArticlepeer-review

Cinzia Imberti, Yu-Lin Chen, Calum A. Foley, Michelle T. Ma, Brett M. Paterson, Yifu Wang, Jennifer Young, Robert C. Hider, Philip J. Blower

Original languageEnglish
Pages (from-to)4299-4313
Number of pages15
JournalDalton Transactions
Issue number13
Early online date12 Mar 2019
Accepted/In press11 Feb 2019
E-pub ahead of print12 Mar 2019
PublishedMay 2019


  • Manuscript_Dalton

    Manuscript_Dalton.pdf, 1.45 MB, application/pdf

    Uploaded date:12 Feb 2019

    Version:Accepted author manuscript

King's Authors


The outstanding efficiency of the tris(hydroxypyridonone) ligand THP Me for radiolabelling PET radiotracers with 68 Ga is surpassed by THP H . The prototype tris(1,6-dimethyl-3-hydroxypyridin-4-one) chelator for gallium-68, THP Me , has shown great promise for rapid and efficient kit-based 68 Ga labelling of PET radiopharmaceuticals. Peptide derivatives of THP Me have been used to image expression of their target receptors in vivo in preclinical and clinical studies. Herein we describe new synthetic routes to the THP platform including replacing the 1,6-dimethyl-3-hydroxypyridin-4-one N 1 –CH 3 group of THP Me with O (tris(6-methyl-3-hydroxypyran-4-one, THPO) and N 1 –H (tris(6-methyl-3-hydroxypyridin-4-one), THP H ) groups. The effect of these structural modifications on lipophilicity, gallium binding and metal ion selectivity was investigated. THP H was able to bind 68 Ga in extremely mild conditions (5 min, room temperature, pH 6, 1 μM ligand concentration) and, notably, in vivo , when administered to a mouse previously injected with 68 Ga acetate. The 67 Ga radiolabelled complex was stable in serum for more than 7 days. [ 68 Ga(THP H )] displayed a log P value of −2.40 ± 0.02, less negative than the log P = −3.33 ± 0.02 measured for [ 68 Ga(THP Me )], potentially due to an increase in intramolecular hydrogen bonding attributable to the N 1 –H pyridinone units. Spectrophotometric determination of the Ga 3+ /Fe 3+ complex formation constants for both THP Me and THP H revealed their preference for binding Ga 3+ over Fe 3+ , which enabled selective labelling with 68 Ga 3+ in the presence of a large excess of Fe 3+ in both cases. Compared to THP Me , THP H showed significantly reduced affinity for Fe 3+ , increased affinity for Ga 3+ and improved radiolabelling efficiency. THPO was inferior to both THP H and THP Me in terms of labelling efficiency, but its benzylated precursor Bn-THPO (tris(6-methyl-3-benzyloxypyran-4-one)) provides a potential platform for the synthesis of a library of THP compounds with tunable chemical properties and metal preferences.

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