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.