Abstract
BackgroundMetastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. The major symptom is severe pain, spinal cord compression, and pathological fracture, associated with an obvious morbidity. Common treatments including systemic application of bisphosphonate drugs aim on pain reduction and on improving the quality of life of the patient. Particularly, patients with multiple metastatic lesions benefit from bone-targeting therapeutic radiopharmaceuticals. Agents utilizing beta-emitting radionuclides in routine clinical praxis are, for example, [89Sr]SrCl2 and [153Sm]Sm-EDTMP. No-carrier-added (n.c.a.) 177Lu is remarkably suitable for an application in this scope.MethodsFive 1,4,7,10-tetraazacyclododecane N,N′,N′′,N′′-tetra-acetic acid (DOTA)- and DO2A-based bisphosphonates, including monomeric and dimeric structures and one 1,4,7-triazacyclononane-1,4-diacetic acid (NO2A) derivative, were synthesized and labelled with n.c.a. 177Lu. Radio-TLC and high-performance liquid chromatography (HPLC) methods were successfully established for determining radiochemical yields and for quality control. Their binding to hydroxyapatite was measured in vitro. Ex vivo biodistribution experiments and dynamic in vivo single photon computed tomography (SPECT)/CT measurements were performed in healthy rats for 5 min and 1 h periods. Data on %ID/g or standard uptake value (SUV) for femur, blood, and soft-tissue organs were analyzed and compared with [177Lu]citrate.ResultsRadiolabelling yields for [177Lu]Lu-DOTA and [177Lu]Lu-NO2A monomeric bisphosphonate complexes were >98 % within 15 min. The dimeric macrocyclic bisphosphonates showed a decelerated labelling kinetics, reaching a plateau after 30 min of 60 to 90 % radiolabelling yields. All 177Lu-bisphosphonate complexes showed exclusive accumulation in the skeleton. Blood clearance and renal elimination were fast. SUV data (all for 1 h p.i.) in the femur ranged from 3.34 to 5.67. The bone/blood ratios were between 3.6 and 135.6, correspondingly. 177Lu-bisphosphonate dimers showed a slightly higher bone accumulation (SUVfemur = 4.48 ± 0.38 for [177Lu]Lu-DO2A(PBP)2; SUVfemur = 5.41 ± 0.46 for [177Lu]Lu-DOTA(MBP)2) but a slower blood clearance (SUVblood = 1.25 ± 0.09 for [177Lu]Lu-DO2A(PBP)2; SUVblood = 1.43 ± 0.32 for [177Lu]Lu-DOTA(MBP)2).ConclusionsLu-complexes of macrocyclic bisphosphonates might become options for the therapy of skeletal metastases in the near future, since they show high uptake in bone together with a very low soft-tissue accumulation.
Highlights
Metastatic bone lesion is a common syndrome of many cancer diseases in an advanced state
We investigated the potential of different 68Ga-labelled DOTA-conjugated bisphosphonates in an animal model as positron emission tomography (PET) imaging agents [22]
Alkylation of DO2A was done by a nucleophilic substitution (2) or by a mannich-like reaction (5), followed by a two-step cleavage (3) of the protection groups, by using trimethylsilyl bromide as a mild and efficient deesterification agent of ethyl-protected bisphosphonates and trifluoroacetic acid for the tert.-butylesters of the carboxylic acid arms
Summary
Metastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. Common treatments including systemic application of bisphosphonate drugs aim on pain reduction and on improving the quality of life of the patient. Patients with multiple metastatic lesions benefit from bone-targeting therapeutic radiopharmaceuticals. Agents utilizing beta-emitting radionuclides in routine clinical praxis are, for example, [89Sr]SrCl2 and [153Sm]Sm-EDTMP. Bone-seeking radiopharmaceuticals showed promising results in the last decades both for diagnosis and therapy [1]. The mechanism of the therapy effect is the synergy of an enhanced accumulation of osteotropic agents on the metastatic lesion and the energy deposit by particle radiation (β−, inner conversion or α-particles). While 89Sr showed unfavorable nuclear properties in terms of β-energy and half-life (βmax = 1.5 MeV, t1/2 = 50 days) [3], new radiopharmaceuticals, like [153Sm]Sm-EDTMP were utilized. Α-emitting [223Ra]RaCl2 was introduced [1]
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