Anticancer Activity of an Imageable Curcuminoid 1-[2-Aminoethyl-(6-hydrazinopyridine-3-carbamidyl)-3,5-bis-(2-fluorobenzylidene)-4-piperidone (EFAH)

3,5-Bis(2-fluorobenzylidine)-4-piperidone or EF24 is a potent anticancer derivative of curcumin. Using an amine derivative of EF24, we synthesized a hydrazinonicotinic acid conjugate, EFAH, for Tc-99m radiolabelling and single photon emission tomography imaging. The aqueous solubility of EFAH (3.5 mg/mL) was significantly more than that of EF24 (1.2 mg/mL); the octanol/water partition coefficient of EFAH was estimated at log P = 0.33. As an antiproliferative agent, EFAH was as effective as EF24 in suppressing the proliferation of H441, MiaPaCa-2 and Panc-1 cells. Daily intraperitoneal injection of EFAH (5 mu g) for 3 weeks in mice carrying xenografts of Panc-1 pancreatic cancer showed a mean tumour volume reduction of 79%; the tumour weight decreased by 82% in the treated group. For imaging and biodistribution, EFAH was labelled with Tc-99m (98% RCY) and intravenously administered in rats. Approximately 23.7% and 14.3% of injected dose accumulated in liver and intestine, respectively, suggesting that EFAH is mostly eliminated by hepatobiliary route. The results indicate that HYNIC modification of EF24 for Tc-99m radiolabelling does not affect its antiproliferative efficacy. For the first time, a visual biodisposition of EF24 in a live animal model has been demonstrated. Such knowledge could be of benefit in developing therapeutic curcuminoids, such as EF24.