Radiosynthesis and biological evaluation of 68Ga-labeled colchicine conjugates

Colchicine, a plant-derived alkaloid, is a known substrate for P-glycoprotein (Pgp), which confers multidrug resistance (MDR) to cancer cells and tumors, through enhanced efflux of chemotherapeutic drugs. Hence, radiolabeled colchicine can be a suitable probe for imaging of activity of Pgp transport in vivo and early diagnosis of MDR.

In the present study, colchicine was hydrolyzed to desacetylcolchiceine for conjugation with p-SCN-Bn-DOTA and p-SCN-Bn-NOTA. The resulting conjugates, DOTA-desacetylcolchiceine and NOTA-desacetylcolchiceine, were radiolabeled with 68Ga. The radiotracers 68Ga-DOTA-desacetylcolchiceine (68Ga-1) and 68Ga-NOTA-desacetylcolchiceine (68Ga-2) were evaluated in vitro (MCF-7 and T47D breast cancer cell lines) and in vivo (biodistribution studies, Swiss mice bearing fibrosarcoma tumors).

The radiotracers prepared in >97% radiochemical yield showed good in vitro binding and significant inhibition with 100-fold cold colchicine (p<0.05). In vivo the tumor uptake reached maximum at 120 minutes postinjection (68Ga-1: 2.35%±0.39% injected dose per gram [ID/g]; 68Ga-2: 1.5%±0.31% ID/g). Of the two radiotracers 68Ga-2 cleared faster from blood (p<0.05) with lower uptake in nontargeted organs as compared with 68Ga-1.

The radiotracer 68Ga-2 has shown improved pharmacokinetic features over 68Ga-1 and the previously reported 99mTc(CO)3-colchicine radiotracer. The preliminary studies with 68Ga-2 indicate its potential for in vivo targeting of tumor. However, the efficacy of the radiotracer for imaging of multidrug-resistant states will be ascertained in future.