Applications of Radiolabelled Curcumin and Its Derivatives in Medicinal Chemistry

Abstract

Curcumin is a natural occurring molecule that has aroused much interest among researchers over the years due to its pleiotropic set of biological properties. In the nuclear medicine field, radiolabelled curcumin and curcumin derivatives have been studied as potential radiotracers for the early diagnosis of Alzheimer's disease and cancer. In the present review, the synthetic pathways, labelling methods and the preclinical investigations involving these radioactive compounds are treated. The studies entailed chemical modifications for enhancing curcumin stability, as well as its functionalisation for the labelling with several radiohalogens or metal radionuclides (fluorine-18, technetium-99m, gallium-68, etc.). Although some drawbacks have yet to be addressed, and none of the radiolabelled curcuminoids have so far achieved clinical application, the studies performed hitherto provide useful insights and lay the foundation for further developments.

Keywords: Alzheimer’s disease; curcumin; curcuminoids; radioactive labelling; radionuclides.

Figure 1

Reagents and conditions: (a) n-Bu₄N[¹⁸F]F, CH₃CN, 120 °C, 15 min; (b) B₂O₃, (n-BuO)₃B, piperidine, ethyl acetate, 120 °C, 20 min, 0.4 N HCl, 90 °C, 5 min; (c) n-Bu₄N[¹⁸F]F, THF, 95 °C, 20 min.

Figure 2

Reagents and conditions: (a) K₂CO₃, Kry2.2.2., [¹⁸F]F⁻, DMSO, 100 °C, 5 min; (b) CuSO₄ (aq), sodium ascorbate (aq), DMSO, RT, 15 min.

Figure 3

Scheme of functionalised NLs embedding [¹⁸F]FTZ-PCur derivative. The figure has been obtained by modifying Figure 1 in reference [39]. Reprinted with permission from [39]. Copyright 2016 Elsevier.

Figure 4

In vivo PET/CT images presenting the whole body biodistribution of [¹⁸F]FTZ-PCur (A), PA-mApoE-[¹⁸F]FTZ-PCur-NLs (B), and TZ-PCur-mApoE-[¹⁸F]FTZ-PCur-NLs (C). Figures present summed PET images taken 30–60 min after injection into a wild-type (WT) mouse. Figure has been obtained by merging and elaborating images drawn from references [36,39]. Reprinted with permission from [36,39]. Copyright 2016 Elsevier.

Figure 5

Reagents and conditions: (a) BF₃·Et₂N, CH₂Cl₂, RT, 3 h; (b) n-Bu₄N[¹⁸F]F, CH₃CN, 110 °C, 10 min; (c) n-butylamine, ethyl acetate, 110 °C, 20 min.

Figure 6

Reagents and conditions: (a) n-Bu₄N[¹⁸F]F, CH₃CN, 110 °C, 10 min; (b) 6 N HCl, 120 °C, 10 min.

Figure 7

In vivo PET images at 65 min of [¹⁸F]FEE-PCur (A) and [¹⁸F]FEEM-PCur (B) in C6 glioma-bearing mice, and at 60 min of [⁶⁸Ga]Ga-DOTA-C21 in a HT29 colorectal tumour-bearing mouse (C). Figure has been obtained by merging and elaborating images from references [50,51]. Reprinted with permission from [50,51]. Copyright 2011 RSC Publishing.

Figure 8

Reagents and conditions: (a) Na[¹²⁵I]I, 1 N HCl, 3% H₂O₂, 10 min; (b) Iodogen, CHCl₃, Na[¹²⁵I]I, RT, 10 min (the product obtained with this path is an assumption of the authors of this review).

Figure 9

Reagents and conditions: (a) curcumin, DMSO 70 °C, 15 min; (b) imidazole, DMSO, 70 °C, 30 min; (c) isocyanocyclohexane, DMSO, RT, 30 min (d) triphenylphosphine, MeOH, RT, 20 min; (e) triphenylphosphine, MeOH, 60 °C, 20 min; (f) triphenylphosphine, MeOH, 60 °C, 20 min.

Figure 10

Reagents and conditions: (a) ⁶⁸Ga³⁺ (0.05 M HCl), 1.5 M CH₃COONa (pH 5), 95 °C, 5 min.

Figure 11

Reagents and conditions: (a) 1, 2-(Boc-amino)ethyl bromide, K₂CO₃, DMF, RT, 48 h, 2, TFA/DCM 2/8, RT, 30 m, 3, DOTA-NHS ester, DIPEA, DMF, 1 h, 4, ⁶⁸Ga³⁺ (0.05 M HCl), 1.5 M CH₃COONa (pH 5), 95 °C, 5 min; (b) 1, 2-(Boc-amino)ethyl bromide, K₂CO₃, DMF, RT, 48 h, 2, TFA/DCM 25/75, RT, 30 m, 3, NODAGA(tBu)₃, HBTU, DIPEA, DMF, 1 h, 4, 80% TFA/DCM, RT, 3 h, 5, ⁶⁸Ga³⁺ (0.05 M HCl), 1.5 M CH₃COONa (pH 5), 95 °C, 5 min; (c) 1. tBuHPC, CH₃COOH, reflux, 6 h, 2, TFA/DCM 25/75, RT, 30 m, 3, AAZTA-HBTU ester, DIPEA, DMF, RT, 8 h, 4, TFA/TIS/H₂O 90/5/5, RT, 2 h, 5, ⁶⁸Ga³⁺ (0.05 M HCl), 1.5 M CH₃COONa (pH 5), RT, 5 min.

Figure 12

Reagents and conditions: (a) n-BuLi, iPr₂NH, THF dry, 0 °C to RT (b) [²H]H₂O or [³H]H₂O, 0.5 h.