In vivo evaluation of [²²⁵Ac]Ac-DOTA^ZOL for α-therapy of bone metastases

Purpose: Abstract Background Conjugates of bisphosphonates (BP) with macrocyclic chelators possess high potential in bone targeted radionuclide imaging and therapy. DOTA^ZOL, zoledronic acid conjugated to DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), demonstrated promising results in vivo in small animals as well as in first patient applications using ⁶⁸Ga for diagnosis via PET and the low-energy β-emitter ¹⁷⁷Lu for therapy of painful bone metastases. In consideration of the fact that targeted α-therapy probably offers various advantages over the use of β^--emitters, the ²²⁵Ac-labelled derivative [²²⁵Ac]Ac-DOTA^ZOL was synthesized and evaluated in vivo. Here we report on biodistribution of [²²⁵Ac]Ac-DOTA^ZOL in healthy Wistar rats, a comparison with [⁶⁸Ga]Ga-DOTA^ZOL and [¹⁷⁷Lu]Lu-DOTA^ZOL and toxicity of [²²⁵Ac]Ac-DOTA^ZOL. Methods DOTA^ZOL was labelled with ²²⁵Ac and injected without further purification into the tail vein with activities of 404 ± 47 kBq per animal. Ex vivo biodistribution studies were performed in healthy Wistar rats at 1 hour, 24 hours, 5 days and 10 days post injection. The accumulation of [²²⁵Ac]Ac-DOTA^ZOL on healthy bone and soft tissue organs was obtained in terms of SUV. The results were compared to those of other radiolabelled bisphosphonates such as [⁶⁸Ga]Ga-DOTA^ZOL and [¹⁷⁷Lu]Lu-DOTA^ZOL. A group of 7 animals was observed over a period of 3 month after application of 394 kBq ± 10 kBq of [²²⁵Ac]Ac-DOTA^ZOL for signs of toxicity. After 3 month kidneys were microscopically analysed for signs of chronic kidney damage. Results Radiolabelling of DOTA^ZOL with ²²⁵Ac at 98 °C provided radiochemical yields ≥98 % within 30 minutes. [²²⁵Ac]Ac-DOTA^ZOL showed high femur uptake (SUV_femur = 4.99 ± 0.97, 10 d p.i.), which was comparable to that of other Me(III)-DOTA^ZOL derivatives. Ratios between bone uptake and blood pool activity reached levels of 5, 940, 2181 and 2409 at 1 hour, 24 hours, 5 days and 10 days post injection. Very low background in terms of accumulation in nontarget tissues was observed for all three tracers. Merely, an appreciable amount of activity in the liver was observed for [²²⁵Ac]Ac-DOTA^ZOL which did not significantly increase over time (SUV_liver = 0.97 ± 0.45, 10 d p.i.). During the observation period of the first two month no toxicity was observed clinically. Slight decline in leukocyte counts in some animals returned to normal at 2 month after application. Also no significant changes were seen in thrombocyte counts or haemoglobin levels. Histopathology of kidneys revealed significant tubular damage in most of the animals. Conclusion [²²⁵Ac]Ac-DOTA^ZOL repeats the well-known pharmacology of DOTA^ZOL derivatives in preclinical evaluations. It thus may be considered for translational application together with strategies to reduce nephrotoxicity.