Gallium(III) complexes of NOTA‐bis (phosphonate) conjugates as PET radiotracers for bone imaging

Holub, Jan; Meckel, Marian; Kubíček, Vojtěch; Rösch, Frank; Hermann, Petr

doi:10.1002/cmmi.1606

Cited by 54 publications

(51 citation statements)

References 52 publications

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“…Therefore, the demand for 68 Ga-labeled compounds for the diagnosis of bone disorders, such as bone metastases, has increased. Some new radiogallium-labeled complexes for bone imaging have been developed in recent years 8 – 14 . Bisphosphonate analogs are used as carriers in these radiogallium-labeled complexes.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Ga-DOTA-(D-Asp)n as bone imaging agents: D-aspartic acid peptides as carriers to bone

Ogawa

Ishizaki

Takai

et al. 2017

Sci Rep

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67Ga-DOTA-(L-Asp)11 and 67Ga-DOTA-(L-Asp)14, which have been developed as bone imaging agents, showed a high accumulation in bone and a rapid blood clearance in mice. However, peptides composed of D-amino acids are more stable in vivo than those composed of their L-equivalents. In this study, 67Ga-DOTA-(D-Asp)n (n = 2, 5, 8, 11, or 14) were synthesized using the Fmoc-based solid-phase methodology and evaluated. In hydroxyapatite binding assay, binding of 67Ga-DOTA-(D-Asp)n tended to increase with increasing length of the amino acid chain. 67Ga-DOTA-(D-Asp)11 and 67Ga-DOTA-(D-Asp)14 caused a high accumulation of radioactivity in the bones of the mice. However, the results for 67Ga-DOTA-(D-Asp)n and 67Ga-DOTA-(L-Asp)n were comparable. In urine analyses, the proportion of intact complex after injection of 67Ga-DOTA-(D-Asp)14 was significantly higher than that of 67Ga-DOTA-(L-Asp)14. Although 67Ga-DOTA-(D-Asp)14 was more stable than 67Ga-DOTA-(L-Asp)14, the properties of 67Ga-DOTA-(D-Asp)n and 67Ga-DOTA-(L-Asp)n as bone imaging agents may be comparable.

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Section: Introductionmentioning

confidence: 99%

Evaluation of Ga-DOTA-(D-Asp)n as bone imaging agents: D-aspartic acid peptides as carriers to bone

Ogawa

Ishizaki

Takai

et al. 2017

Sci Rep

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“…Gallium-based radiopharmacy of CDTMP overcomes the need of in-house cyclotron facility as well as enhanced spatial resolution, and quantification properties of PET technique are much superior to conventional SPECT technique. Much advanced imaging results of PET/CT, as compared to SPECT/CT, are clearly demonstrated by using [ 18 F]-fluoride (18). …”

Section: Discussionmentioning

confidence: 99%

[68Ga]/[188Re] Complexed [CDTMP] Trans-1,2-Cyclohexyldinitrilotetraphosphonic Acid As a Theranostic Agent for Skeletal Metastases

et al. 2017

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ObjectiveMetastasis of the osseous tissue is one of the frequent and severe aggravations as a result of several neoplastic conditions, such as metabolic disorders, infections, and cancer. The objective of this study was to evaluate the pertinence of [68Ga]-trans-1,2-cyclohexyldinitrilo tetramethylene phosphonic acid (CDTMP) as a potential bone imaging agent for positron emission tomography (PET) applications as well as to assess [188Re]-CDTMP for bone pain palliation in metastatic skeletal disorders.Methods68Ga complex of CDTMP was prepared at 80°C at pH 3.5, and 188Re complex of CDTMP was prepared at room temperature. [68Ga]-CDTMP complex was investigated as PET tracer while the therapeutic efficacy was assessed for [188Re]-CDTMP. Labeling efficiency, biodistribution, myelotoxicity, and imaging studies were carried out for the complexes synthesized. Both PET and MicroPET imaging studies were performed for [68Ga]-CDTMP whereas SPECT acquisitions were acquired for [188Re]-CDTMP. Data were analyzed semiquantitatively for all the scintigraphic scans obtained.ResultsThe radiolabeling efficiency was observed to be >70% for [68Ga]-CDTMP. High bone uptake of [68Ga]-CDTMP as compared to contralateral tissue was found in PET imaging in Balb/C mice and New Zealand rabbit; the similar result for bone uptake was correlated in the biodistribution study of the compound in BALB/c mice at different time intervals. Biodistribution experiments carried out in mice showed maximum uptake of 6.12 ± 1.22%ID/g at 45 min postinjection. For [188Re]-CDTMP, total skeletal uptake was 8.12 ± 1.11%ID/g observed at 1 h postinjection from biodistribution data. High renal uptake confirms renal route of excretion. A good hydroxyapatite binding too was seen for both the complexes. No evidence of destruction or adverse functioning of vital organs was observed for the 188Re complex.Conclusion[68Ga]-CDTMP complex can be used as a promising PET bone imaging agent and [188Re]-CDTMP as a surrogate moiety for therapeutic application. Owing to the short half-life of 68Ga (68 min), cyclotron-independent radiopharmacy, fast clearance, and rapid renal excretion as evidenced in preclinical animal models. Very low myelotoxicity and highly selective bone uptake prove the potential of [188Re]-CDTMP for therapeutic application.

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“…Within this study, BPAMD showed to be a potential bone-targeting agent to treat skeletal metastases with 177 Lu. Contrary to other actual discussed tracers like EDTMP, BPAMD proved to be an efficient 68 Ga-PET imaging agent for bone metastasis [ 21 ]. Neither [ 177 Lu/ 153 Sm]Lu/Sm-EDTMP nor [ 223 Ra]RaCl 2 offer this theranostic approach.…”

Section: Discussionmentioning

confidence: 99%

“…1,4,7,10-tetraazacyclododecane-1,7-bis-tert.butyl diacetic acid ester (tert.butyl-DO2A) [ 26 ], tetraethyl chloro-acetamidomethyl-bis(phosphonate) ( 1 ), tetraethyl{[(ethoxyhydrophosphoryl)methyl]methylene} bis(phosphonate) ( 4 ) and the compounds DOTAM BP , DO3AP BP , DOTAM EBP , and NO2AP BP were synthesized according to the published literature [ 21 , 27 , 28 ].…”

Section: Methodsmentioning

confidence: 99%

“…[ 68 Ga]BPAMD PET/CT showed uptake values on disseminated bone metastases as high as 18 F-fluoride, sometimes even superior [ 20 ]. Recently, the NOTA-derivative [ 68 Ga]NO2AP BP was identified to show even improved imaging quality [ 21 ]. In a previous work, we investigated the potential of different 68 Ga-labelled DOTA-conjugated bisphosphonates in an animal model as PET imaging agents [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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177Lu-labelled macrocyclic bisphosphonates for targeting bone metastasis in cancer treatment

et al. 2016

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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.

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Gallium(III) complexes of NOTA‐bis (phosphonate) conjugates as PET radiotracers for bone imaging

Cited by 54 publications

References 52 publications

Evaluation of Ga-DOTA-(D-Asp)n as bone imaging agents: D-aspartic acid peptides as carriers to bone

Evaluation of Ga-DOTA-(D-Asp)n as bone imaging agents: D-aspartic acid peptides as carriers to bone

[68Ga]/[188Re] Complexed [CDTMP] Trans-1,2-Cyclohexyldinitrilotetraphosphonic Acid As a Theranostic Agent for Skeletal Metastases

177Lu-labelled macrocyclic bisphosphonates for targeting bone metastasis in cancer treatment

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