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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s41181-016-0017-1) contains supplementary material, which is available to authorized users.