DOTA^ZOL and NODAGA^ZOL for theranostics of bone metastases

Objectives: Conjugates of bisphosphonates (BPs) with macrocyclic chelators already showed promising results for the diagnosis and radiotherapy of painful bone metastases. Based on zoledronic acid, the currently most potent BP, DOTA^ZOL demonstrated high potential especially for the endoradiotherapy with the low-energy β-emitter Lu-177 in first patient studies. A NODAGA based zoledronic acid derivative shall now simplify radiolabeling with Ga-68 for the diagnosis of skeletal lesions via PET. Here we report on the in vivo comparison of Ga-68-labeled DOTA^ZOL and NODAGA^ZOL in healthy Wistar rats to investigate their potential as a theranostic pair for bone metastases.

Methods: DOTA^ZOL and NODAGA^ZOL were labeled with Ga-68 to compare the biodistribution of the labeled compounds in healthy male Wistar rats. For each compound 6.3 ± 0.5 MBq were injected via the tail vein (n = 4 per time point). Biodistribution studies were performed 5 and 60 min p.i.. Dynamic PET scans were carried out for both compounds (n = 1) over 120 min.

Results: While labeling of DOTA^ZOL with Ga-68 only provided 80-90 % radiochemical yield after 15 minutes at 98 °C, Ga-68-NODAGA^ZOL showed the expected quantitative labeling within 10 minutes at 98 °C. Both tracers exhibited low uptake in soft tissue, fast renal clearance and high bone accumulation in the biodistribution studies. Ga-68-NODAGA^ZOL had a higher femur accumulation 5 minutes p.i. (SUV = 3.51 ± 0.17 vs. SUV = 2.89 ± 0.44) as well as 60 minutes p.i. (SUV = 4.53 ± 0.28 vs. SUV = 3.67 ± 0.37). Target to background ratios were also superior for the NODAGA derivative (femur/blood = 57 ± 5 vs. 8.4 ± 1.4, femur/muscle = 160 ± 66 vs. 45 ± 6, 60 min p.i.). PET scans showed very high uptake of both labeled compounds in the high metabolic epiphysis (SUV = 26.9 vs. SUV = 17.4 for Ga-68-NODAGA^ZOL vs. Ga-68-DOTA^ZOL, respectively) which allows prognoses about the tracers’ accumulation in skeletal lesions.

Conclusion: The Ga-68-labeled NODAGA based zoledronic acid derivative NODAGA^ZOL shows quantitative labeling and does not require subsequent purification. Both Ga-68-NODAGA^ZOL and Ga-68-DOTA^ZOL exhibit high bone accumulation, low uptake in soft tissue and fast renal clearance. Bone accumulation was higher for NODAGA^ZOL compared to DOTA^ZOL, which matches the experimental data obtained earlier for Ga-68-NO2AP^BP vs. Ga-68-BPAMD. Considering the potential of DOTA^ZOL for endoradiotherapy with Lu-177, Ga-68-NODAGA^ZOL appears to become the diagnostic arm for the theranostic pair for bone metastases. Research Support: