Bone targeting compounds for radiotherapy and imaging: *Me(III)-DOTA conjugates of bisphosphonic acid, pamidronic acid and zoledronic acid.

Background: Bisphosphonates have a high adsorption on calcified tissues and are commonly used in the treatment of bone disorder diseases. Conjugates of bisphosphonates with macrocyclic chelators open new possibilities in bone targeted radionuclide imaging and therapy. Subsequent to positron emission tomography (PET) examinations utilizing ⁶⁸ Ga-labelled analogues, endoradiotheraphy with ¹⁷⁷ Lu-labelled macrocyclic bisphosphonates may have a great potential in the treatment of painful skeletal metastases.
Methods: Based on the established pharmaceuticals pamidronate and zoledronate two new DOTA-α-OH-bisphosphonates, DOTA ^PAM and DOTA ^ZOL (MM1.MZ) were successfully synthesized. The ligands were labelled with the positron emitting nuclide ⁶⁸ Ga and the β ^- emitting nuclide ¹⁷⁷ Lu and compared in in vitro studies and in ex vivo biodistribution studies together with small animal PET and single photon emission computed tomography (SPECT) studies against [ ¹⁸ F]NaF and a known DOTA-α-H-bisphosphonate conjugate (BPAPD) in healthy Wistar rats.
Results: The new DOTA-bisphosphonates can be labelled in high yield of 80 to 95 % in 15 min with post-processed ⁶⁸ Ga and >98 % with ¹⁷⁷ Lu. The tracers showed very low uptake in soft tissue, a fast renal clearance and a high accumulation on bone. The best compound was [ ⁶⁸ Ga]DOTA ^ZOL (SUV _Femur  = 5.4 ± 0.6) followed by [ ¹⁸ F]NaF (SUV _Femur  = 4.8 ± 0.2), [ ⁶⁸ Ga]DOTA ^PAM (SUV _Femur  = 4.5 ± 0.2) and [ ⁶⁸ Ga]BPAPD (SUV _Femur  = 3.2 ± 0.3). [ ¹⁷⁷ Lu]DOTA ^ZOL showed a similar distribution as the diagnostic ⁶⁸ Ga complex.
Conclusion: The ⁶⁸ Ga labelled compounds showed a promising pharmacokinetics, with similar uptake profile and distribution kinetics. Bone accumulation was highest for [ ⁶⁸ Ga]DOTA ^ZOL , which makes this compound probably an interesting bone targeting agent for a therapeutic approach with ¹⁷⁷ Lu. The therapeutic compound [ ¹⁷⁷ Lu]DOTA ^ZOL showed a high target-to-background ratio. SPECT experiments showed concordance to the PET scans in healthy rats. [ ⁶⁸ Ga/ ¹⁷⁷ Lu]DOTA ^ZOL appears to be a potential theranostic combination in the management of disseminated bone metastases.