Radiosynthesis and Biological Evaluation of 68 Ga-Labeled Colchicine Conjugates

Abstract

Objective:

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.

Methods:

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).

Results:

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.

Conclusions:

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.