Abstract
BackgroundBisphosphonates 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 68Ga-labelled analogues, endoradiotheraphy with 177Lu-labelled macrocyclic bisphosphonates may have a great potential in the treatment of painful skeletal metastases.MethodsBased on the established pharmaceuticals pamidronate and zoledronate two new DOTA-α-OH-bisphosphonates, DOTAPAM and DOTAZOL(MM1.MZ) were successfully synthesized. The ligands were labelled with the positron emitting nuclide 68Ga and the β- emitting nuclide 177Lu 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 [18F]NaF and a known DOTA-α-H-bisphosphonate conjugate (BPAPD) in healthy Wistar rats.ResultsThe new DOTA-bisphosphonates can be labelled in high yield of 80 to 95 % in 15 min with post-processed 68Ga and >98 % with 177Lu. The tracers showed very low uptake in soft tissue, a fast renal clearance and a high accumulation on bone. The best compound was [68Ga]DOTAZOL (SUV Femur = 5.4 ± 0.6) followed by [18F]NaF (SUV Femur = 4.8 ± 0.2), [68Ga]DOTAPAM (SUV Femur = 4.5 ± 0.2) and [68Ga]BPAPD (SUV Femur = 3.2 ± 0.3). [177Lu]DOTAZOL showed a similar distribution as the diagnostic 68Ga complex.ConclusionThe 68Ga labelled compounds showed a promising pharmacokinetics, with similar uptake profile and distribution kinetics. Bone accumulation was highest for [68Ga]DOTAZOL, which makes this compound probably an interesting bone targeting agent for a therapeutic approach with 177Lu. The therapeutic compound [177Lu]DOTAZOL showed a high target-to-background ratio. SPECT experiments showed concordance to the PET scans in healthy rats. [68Ga/177Lu]DOTAZOL appears to be a potential theranostic combination in the management of disseminated bone metastases.
Highlights
Bisphosphonates have a high adsorption on calcified tissues and are commonly used in the treatment of bone disorder diseases
Synthesis Synthesis of BPAPD is published in the literature (Vitha et al 2008) as well as the synthesis of pamidronate (Kieczykowski et al 1995)
A convenient method to discriminate between the 1,4- and the 1,5-alkylation product is described in the literature by the different coupling constants of the aromatic imidazole ring protons (Amino et al 1989). (2) showed a coupling constant of J2,5 = 1.3 Hz, which is characteristic for the 1,4-product
Summary
Bisphosphonates have a high adsorption on calcified tissues and are commonly used in the treatment of bone disorder diseases. Positron emission tomography (PET) has one of the highest diagnostic sensitivity and specificity for the detection of skeletal metastases (Hamaoka et al 2004), when used with the cyclotron produced [18F]NaF. The positron emitter 68Ga has several advantages, which makes it an interesting object in the development of radiopharmaceuticals First of all it is the cyclotron independent availability based on the 68Ge/68Ga generator system—similar to the availability of 98mTc, and second, it is the intense emission of positrons—similar to 18F. It is the principle of the bifunctional chelating agent to design radiometal, in particular *Me(III), based pharmaceuticals. In addition Passah et al reported the use of a bisphosphonate conjugated to NOTA (1,4,7,10-tetraazacyclododecane1,4,7,10-tetraacetic acid) chelator to detect bone metastases efficiently (Passah et al 2014; Pfannkuchen et al 2015)
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