Synthesis and Characterization of 68Ga-Labeled Curcumin and Curcuminoid Complexes as Potential Radiotracers for Imaging of Cancer and Alzheimer's Disease

Curcumin (CUR) and curcuminoids complexes labeled with fluorine-18 or technetium-99m have recently shown their potential as diagnostic tools for Alzheimer's disease. Gallium-68 is a positron-emitting, generator-produced radionuclide, and its properties can be exploited in situ in medical facilities without a cyclotron. Moreover, CUR showed a higher uptake in tumor cells compared to normal cells, suggesting potential diagnostic applications in this field. In spite of this, no studies using labeled CUR have been performed in this direction, so far. Herein, Ga-68-labeled complexes with CUR and two curcuminoids, namely diacetyl-curcumin (DAC) and bis(dehydroxy)curcumin (bDHC), were synthesized and characterized by means of experimental and theoretical approaches. Moreover, a first evaluation of their affinity to synthetic beta-amyloid fibrils and uptake by A549 lung cancer cells was performed to show the potential application of these new labeled curcuminoids in these diagnostic fields. The radiotracers were prepared by reacting Ga-68(3+) obtained from a Ge-68/Ga-68 generator with 1 mg/mL curcuminoids solutions. Reaction parameters (precursor amount, reaction temperature, and pH) were optimized to obtain high and reproducible radiochemical yield and purity. Stoichiometry and formation of the curcuminoid complexes were investigated by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, NMR, ultraviolet visible, and fluorescence spectroscopy on the equivalent Ga-nat-curcuminoids (flat = natural) complexes, and their structure was computed by theoretical density functional theory calculations. The analyses evidenced that CUR, DAC, and bDHC were predominantly in the keto-enol form and attested to Ga(L)(2)(+) species formation. Identity of the Ga-68(L)(2)(+) complexes was confirmed by coelution with the equivalent Ga-nat(L)(2)(+) complexes in ultrahigh-performance liquid chromatography analyses.Ga-68(CUR)(2)(+), Ga-68(DAC)(2)(+), and Ga-68(bDHC)(2)(+) were highly (87 +/- 4, 90 +/- 1%) and moderately (48 +/- 2%), respectively, retained by synthetic beta-amyloid fibrils in vitro. All the Ga-curcuminoid complexes showed an uptake in A549 lung cancer cells, at least equivalent to the respective free curcuminoids, confirming potential applications as cancer-detecting radiotracers.