Patent Abstract:
methods of using th - 226 or mother radionuclides thereof , namely u - 230 or th - 226 , in medicine . these radionuclides are particularly appropriate for the treatment of human and / or non - human mammals , in particular for therapeutic , diagnostic , prophylactic and pain palliation purposes . these radionuclides may be used in various forms for treatment and / or diagnostic purposes , in particular in cationic form or in the form of radioconjugates or bone - targeting complexes . methods of making such radionuclides .

Detailed Description:
the present invention proposes the use of the radionuclide th - 226 as well as mother radionuclides of th - 226 for medical purposes . among the mother radionuclides of th - 226 , u - 230 and ac - 226 are particularly preferred for their advantageous properties . the set of radionuclides comprising th - 226 , u - 230 and ac - 226 has been found to be optimally suited for use in medicine . in the following , the use of these three radionuclides in the medical field will be described in more detail . their favourable decay characteristics , their use in the manufacture of radiopharmaceuticals , their ease of production at high efficiency and purity levels as well as their advantageous complexing and chelating properties will be discussed in the following by way of detailed examples . the radionuclides u - 230 , th - 226 and ac - 226 have decay characteristics that favour their use in medical applications . u - 230 and th - 226 are alpha - emitters with half - lives of 20 . 8 days and 31 minutes , respectively . the decay chain of u - 230 is shown in fig1 . both nuclides are pure alpha - emitters that produce 5 and 4 alpha particles , respectively , with a cumulative energy of 33 . 6 and 27 . 7 mev , until they decay to the relatively long lived beta - emitter pb - 210 ( half - life : 22 . 3 years ). all alpha - emitting daughter nuclides of th - 226 are short - lived and do not emit high - energy gamma lines that would require extensive shielding . however , th - 226 and its daughter nuclide ra - 222 emit gamma rays in the low energy range from 80 - 350 kev that is ideal for imaging of the biodistribution of the nuclides in the body . th - 226 and ra - 222 emit gamma rays with energy of 111 kev with an emission probability of 3 . 3 % and with energy of 324 kev with an emission probability of 2 . 8 %, respectively . u - 230 can either be used directly for medical purposes or can be utilised as a parent nuclide for the production of th - 226 . to this end u - 230 can be fixed on a radionuclide generator ( extraction chromatographic material or ion exchanger ) that allows the selective elution of th - 226 at regular or determined time intervals . ac - 226 has a half - life of 29 h and decays through β − emission with a branching ratio of 83 % to th - 226 . it also decays through positron emission ( 0 . 64 mev ) with a branching ratio of 17 % to ra - 226 as well as through alpha - decay to fr - 222 with a low branching ratio of 6 · 10 − 3 %. the decay chain of ac - 226 is shown in fig2 . due to the longer half - life of ac - 226 ( t 1 / 2 = 29 . 4 hours ) compared to th - 226 ( t 1 / 2 = 31 min ), a radiopharmaceutical containing ac - 226 can be used to target cells that are less readily accessible than in the case of using th - 226 . the decay of ac - 226 will produce in situ short lived th - 226 with its favourable decay characteristics and the emission of multiple alpha - particles , resulting in the delivery of a highly cytotoxic dose to targeted cells . the distribution of ac - 226 in the body can be detected using positron emission tomography . ac - 226 can either be used directly for medical purposes or can be utilised as a mother radionuclide for the production of th - 226 . to this end ac - 226 can be fixed on a radionuclide generator ( extraction chromatographic material or ion exchanger ) that allows the selective elution of th - 226 in regular time intervals . although various methods could be used to produce u - 230 , ac - 226 and th - 226 , preferred production methods are described below . a first , well known production route for u - 230 has been proposed by koua aka et al . [ ref . 13 ] and is based on the irradiation of natural th - 232 with protons of appropriate energy according to the reaction th - 232 ( p , 3n ) pa - 230 , the obtained pa - 230 decaying into u - 230 . pa - 230 is a beta emitter ( β + and β − ) with a half - life of 17 . 4 days that decays to u - 230 with a branching ratio of 8 . 4 %. the production of approx . 0 . 8 mci of u - 230 by irradiation of thick th - 232 targets has been reported by koua aka et al . two alternatives of producing u - 230 by the irradiation of natural th - 232 are also proposed . according to a first alternative process , u - 230 can be obtained from the decay of pa - 230 produced according to the reaction th - 232 ( d , 4n ) pa - 230 . u - 230 is thus indirectly obtained by the radioactive decay of pa - 230 . taking into account that according to model calculations using the alice code ( lawrence livermore national laboratory , usa ), the maximum cross sections for the reaction th - 232 ( d , 4n ) pa - 230 ( 1290 mb at 24 mev ) is similar to the maximum cross section for the reaction th - 232 ( p , 3n ) pa - 230 ( 1260 mb at 22 mev ), a similar production yield can be expected using deuteron irradiation of u - 230 ( fig4 and table 1 ). the energy of the deuterons will preferably be adjusted such that the energy incident on th - 232 is between 20 and 35 mev . in the second alternative process , u - 230 is produced directly by irradiation of th - 232 with helium nuclei . according to the reaction th - 232 ( α , 6n ) u - 230 , u - 230 can be produced in a direct manner . the energy of the helium particles is preferably adjusted such that the energy incident on th - 232 is between 50 and 70 mev , more preferably between 53 and 65 mev . taking into account the theoretical cross sections of the reactions th - 232 ( p , 3n ) pa - 230 ( 1260 mb at 22 mev ) and th - 232 ( α , 6n ) u - 230 ( 1000 mb at 57 mev ), and also taking into account that u - 230 is produced directly using the latter reaction , overall a 23 . 6 - fold enhancement of production yield can be expected using the irradiation of th - 232 by helium particles compared to the current state - of - the - art method ( fig7 and table 1 ). for the production of u - 230 by irradiation of th - 232 , preferably thorium metal will is used as target material , but also thorium targets prepared by electrode - position or thorium oxide or other suitable thorium materials can be used . the th - 232 target material is preferably placed in a capsule and / or any other suitable sealed container , e . g . made of silver or aluminium and cooled by a closed water circuit . it is to be noted that the production of u - 230 from th - 232 by proton or deuteron irradiation may , depending on the incident proton or deuteron beam energy also lead to the production of ac - 225 . indeed , it has been observed that irradiation of th - 232 by hydrogen isotope nuclei can also be used as an alternative method for the production of ac - 225 . pa - 229 , obtained according to the reactions th - 232 ( p , 4n ) pa - 229 or th - 232 ( d , 5n ) pa - 229 , respectively , is decaying via emission of an alpha particle with a branching ratio of 0 . 48 % into ac - 225 . the proton energy will preferably be adjusted such that the energy incident on th - 232 is between 19 and 40 mev ( fig4 ). the deuteron energy will preferably be adjusted such that the energy incident on th - 232 is between 25 and 50 mev ( fig4 ). taking into account the theoretical cross sections for the reactions th - 232 ( p , 4n ) pa - 229 and th - 232 ( d , 5n ) pa - 229 as shown in fig4 , the production of approx . 5 μci ac - 225 per μah can be expected for the irradiation of thick th - 232 targets by protons or deuterons of the appropriate energy . as an example , by irradiation of a thick th - 232 target for 100 hours using a proton or deuteron current of 100 μa the production of approx . 50 mci of ac - 225 can be expected . the production of ac - 225 by irradiation of th - 232 has several important advantages over the known production methods which are based on the irradiation of ra - 226 by hydrogen nuclei . these advantages include preparation , handling and transport of targets as well as greatly reduced safety risks associated with the irradiation of low - radioactive thorium as compared to the irradiation of highly radioactive ra - 226 . the present invention proposes another advantageous method for producing u - 230 , which is based on the irradiation of pa - 231 with hydrogen isotope nuclei . this process is preferably carried out in a cyclotron , wherein the energy of the incident beam can be adjusted to optimal values . for irradiation with protons , the proton energy is preferably adjusted such that the energy incident on the pa - 231 target is between 10 and 25 mev , more preferably between 13 and 17 mev . for irradiation with deuterons , the deuteron energy is preferably adjusted such that the energy incident on the pa - 231 target is between 10 and 25 mev , more preferably between 18 and 21 mev . through the reactions proposed in this invention : pa - 231 ( p , 2n ) u - 230 and pa - 231 ( d , 3n ) u - 230 , u - 230 can be produced directly , while through the reaction th - 232 ( p , 3n ) pa - 230 , u - 230 is produced only as decay product of pa - 230 with a maximal theoretical yield of 3 . 37 wt . % relative to the amount of pa - 230 produced . taking into account that according to model calculations using the alice code ( lawrence livermore national laboratory , usa ), the maximum cross sections for the reaction pa - 231 ( p , 2n ) u - 230 ( 634 mb at 15 mev , fig3 ) is approx . 2 times lower than the maximum cross section for the reaction th - 232 ( p , 3n ) pa - 230 ( 1260 mb at 22 mev , fig4 ), overall a 14 . 9 - fold enhancement of production yield can be expected using proton irradiation of pa - 231 . the maximum cross section for the reaction pa - 231 ( d , 3n ) u - 230 ( 1160 mb at 18 . 5 mev , fig5 ) is similar to the maximum cross - section for the reaction th - 232 ( p , 3n ) pa - 230 , therefore even an overall 27 . 3 - fold enhancement of production yield can be expected using deuteron irradiation of pa - 231 compared to the method described by koua aka et al . [ ref . 13 ] ( see table 2 ). since the direct production of u - 230 by proton or deuteron irradiation of pa - 231 is expected to be approx . 15 and 27 times , respectively , more efficient than the state - of - the - art method for the production of u - 230 ( ref . 13 ), using the production methods of the invention permits a significant increase in the amounts of u - 230 and th - 226 that can be made available for pre - clinical and clinical studies . additionally , since a significant cost factor in the production of radioisotopes in a cyclotron is related to the required irradiation time , the production methods proposed in this invention can lead to a significant reduction of production costs . for irradiation , the pa - 231 target material is preferably placed in a capsule and / or any other suitable container and cooled by a closed water circuit . the protactinium may be in metallic form ( e . g . electrodeposited pa ) or oxidized form . the capsule , e . g . made of silver or aluminium , provides a sealed container for the radioactive pa - 231 , allows target processing after irradiation without introducing impurities into the medical grade product and avoids the introduction of undesired cations that would interfere with the chelation of the radionuclides . after irradiation , uranium is separated from the irradiated target material , preferably by chemical separation , using e . g . conventional techniques . chemical separation can be performed using ion exchange , extraction chromatography and / or sorption to silica gel . it is to be noted that the fabrication and irradiation of targets containing pa - 231 requires to some extent increased safety measures compared to low - radioactive th - 232 . however , the availability of suitable protactinium materials , including protactinium metal or protactinium oxide , which have a very low solubility in water , is adding an inherent safety to the irradiation process , since even in the case of target failure only minute amounts of target material would be dissolved in the cooling circuit . a preferred method for the production of ac - 226 is based on the irradiation of ra - 226 targets using deuterons or protons , according to the reactions ra - 226 ( d , 2n ) ac - 226 and ra - 226 ( p , n ) ac - 226 , respectively . irradiation with deuterons is more preferred as it permits an increased production yield . fig6 shows the calculated cross - sections of the reaction ra - 226 ( d , xn ) ac for the isotopes ac - 225 , ac - 226 and ac - 227 in function of deuteron energy ( x being equal to 1 , 2 or 3 respectively ). a preferred deuteron energy is between 5 and 15 mev . however , as can be seen from the model calculations in fig6 , the production of ac - 226 can be expected to be enhanced with respect to other radioisotopes when the incident deuteron energy is adjusted between 10 and 12 mev . for irradiation with protons , the proton energy is preferably adjusted such that the energy incident on the ra - 226 target is between 5 and 15 mev , more preferably between 8 and 12 mev . as is the case for u - 230 , the production of ac - 226 is preferably carried out in a cyclotron . the ra - 226 target material preferably is in the form racl 2 , which has been dried and pressed into pellets . to facilitate the handling of the highly toxic ra - 226 target material , the latter is advantageously placed in a sealed capsule of silver or aluminium . if aluminium is used as capsule material , the target material is preferably placed in an envelope made of ag , ti or nb before introduction into the capsule , so as to avoid contamination of the target material with aluminium , in particular during post - irradiation treatments . ag , ti and nb have a high conductivity and thus allow for a high deuteron current density during irradiation . nb is particularly preferred for its low ionising radiation emissions after irradiation . after irradiation , actinium is preferably chemically separated from the irradiated target of ra - 226 . separation of actinium from irradiated radium can be achieved using ion exchange or extraction chromatography , e . g . using the extraction chromatographic resin ln - spec ( by eichrom technologies inc ., usa ). to this end the irradiated radium chloride target is dissolved in 0 . 01 m hcl and the resulting solution is loaded onto a column filled with ln - spec . subsequently radium is washed though the column using 0 . 1 m hcl , while actinium remains on the column . the radium eluate is conditioned to be used again for target preparation . actinium is stripped off the column using 2 m hcl and directly loaded onto a sr - spec ( by eichrom technologies inc .) column for further purification . actinium is washed through the sr - spec column using 2 m hcl and converted into the appropriate matrix for subsequent production of preparations for radiotherapy . in view of the advantageous production routes proposed above , it thus appears that it is interesting to use th - 226 originating therefrom in the context of the present invention . u - 230 or ac - 226 can be used as source for th - 226 . therefore , the mother radionuclide ( u - 230 or ac - 226 ) is loaded on a separation column filled with an appropriate material , e . g . an extraction chromatographic resin or an ion exchange material that allows selective elution of th - 226 at appropriate time intervals . u - 230 is loaded onto a column containing the extraction chromatographic material teva ® ( eichrom technologies inc . ; this material includes as active component an aliphatic quaternary amine ) from hydrochloric acid solution , e . g . 6 m hydrochloric acid . preferentially , silica gel is used as inert support material for the extraction chromatographic material teva ® in order to increase the radiation resistance of the generator material and to minimise its radiolytic degradation . th - 226 can be eluted from the generator using 6 m hydrochloric acid with a yield of approx . 90 % in 4 - 6 column bed volumes , while u - 230 remains on the generator . a peristaltic pump can be used for the elution of the generator to facilitate automation of the elution process . it has been observed that more than 100 elutions of thorium using 4 - 6 bed volumes of 6 m hcl could be performed from a u / th radionuclide generator consisting of teva ® extraction chromatographic material without significant breakthrough of uranium into the thorium eluate . it will thus be appreciated that teva ® extraction chromatographic resin , preferentially containing silica gel as inert support material , shall be advantageously used to prepare an uranium / thorium radionuclide generator . in the following , the preparation of radiopharmaceuticals containing u - 230 , th - 226 or ac - 226 is treated separately for each radionuclide . as it will appear , these radiopharmaceuticals provide a broad medical application field . for illustrative purposes , the preparation of radiopharmaceuticals including these radionuclides for use in targeted radiotherapy , pre - targeted radiotherapy and for bone - targeting is described in detail , by way of example . as described above , separation of u - 230 from irradiated th - 232 or pa - 231 targets can be performed using known chemical separation techniques , including ion exchange , extraction chromatography and sorption to silica gel . for the preparation of radiopharmaceuticals containing u - 230 , purified u - 230 is preferably dissolved in a first step in dilute acid , preferentially hydrochloric or nitric acid . a u - 230 radiopharmaceutical for targeted radiotherapy is prepared as follows . the radionuclide u - 230 is mixed with a buffered solution of a chelated carrier molecule in e . g . using sodium acetate buffer at ph 5 - 7 and incubated for an appropriate time , e . g . 1 hour . purification of the u - 230 radioconjugate can be performed using size exclusion chromatography or ion exchange procedures , followed by sterile filtration . a pharmaceutically acceptable carrier or excipient can be added and / or a scavenging agent . for the use of u - 230 in pre - targeted radiotherapy , the radionuclide is mixed with a buffered solution of chelated biotin or another suitable carrier molecule and incubated for an appropriate time . purification of the obtained u - 230 radioconjugates can be performed using high performance liquid chromatography or ion exchange procedures and sterile filtration . representative conditions for forming radioconjugates are given here . to a solution containing u - 230 in 0 . 2 m ammonium acetate , ph 5 . 0 , containing approximately 10 mg / ml of ascorbic acid as a radioprotectant , 2 μg of chelated biotin in 1 μl of 0 . 2 m ammonium acetate , ph 5 . 0 , are added . the reaction mixture is incubated for 1 h , after which 10 μl of a solution containing 1 . 5 mg / ml dtpa , ph 5 . 0 , are added . the reaction mixture is incubated at room temperature for 60 min , after which radiochemical purity is determined by thin layer chromatography . a pharmaceutically acceptable carrier or excipient can be added as well as a scavenging agent . for the use of u - 230 for bone - targeting , the solution containing u - 230 will subsequently be mixed with a solution of an appropriate complexing agent to form a bone - seeking complex . purification of the final product can be performed using ion exchange procedures and sterile filtration . the radiopharmaceutical comprising the present u - 230 bone targeting complexes may further comprise a pharmaceutically acceptable carrier or excipient . for the preparation of th - 226 - labelled radiopharmaceuticals used for targeted alpha therapy , the eluate of th - 226 in 6 m hydrochloric acid is neutralised using sodium hydroxide , buffered to an appropriate ph value , preferentially between 5 and 7 using e . g . sodium acetate , mixed with a solution containing a chelated carrier molecule ( targeting moiety ) and incubated for an appropriate time , preferentially 1 - 5 minutes . purification of the obtained th - 226 - radioconjugates can be performed using size exclusion chromatography or ion exchange procedures and sterile filtration . the radiopharmaceutical comprising the th - 226 radioconjugates may additionally comprise a pharmaceutically acceptable carrier or excipient and / or a scavenging agent . representative conditions for coupling by chelation are given here : to 500 μl of th - 226 - eluate in 6 m hcl , a mixture of 300 μl 10 m naoh , 200 μl 2 m sodium acetate buffer and 100 μl of 10 % ascorbic acid solution as radioprotectant is added to adjust the ph to a value of 5 - 6 . following addition of 100 μg of bz - dtpa - antibody in buffered solution , the solution is incubated for 3 minutes . subsequently 10 μl of a solution containing 1 . 5 mg / ml dtpa are added to quench the chelation reaction . immediately after dtpa - addition , the radioimmunoconjugates are purified by size - exclusion chromatography and passed through a sterile filter . for the use of th - 226 in pre - targeted alpha therapy , the radionuclide is mixed with a buffered solution of chelated biotin or another suitable carrier molecule and incubated for an appropriate time . purification of the th - 226 - radioconjugate can be performed using ion exchange procedures and sterile filtration . representative conditions for coupling by chelation are given here . to a solution containing th - 226 in 0 . 2 m ammonium acetate , ph 5 . 0 , containing approximately 10 mg / ml of ascorbic acid as a radioprotectant , 2 μg of bz - dtpa - biotin in 1 μl of 0 . 2 m ammonium acetate , ph 5 . 0 , are added . the reaction mixture is incubated for 3 min , after which 10 μl of a solution containing 1 . 5 mg / ml dtpa , ph 5 . 0 , is added . immediately after dtpa - addition , the biotin targeted radioconjugate is purified and passed through a sterile filter . for the use of th - 226 for bone - targeting , the generator eluate containing th - 226 is neutralised , buffered and mixed with a solution of an appropriate complexing agent , e . g . phosphonic acid complexants and more specifically 1 , 4 , 7 , 10 tetraazacyclododecane n , n , n ″, n ″′ 1 , 4 , 7 , 10 - tetra ( methylene ) phosphonic acid ( dotmp ) or thorium - diethylenetriamine n , n ′, n ″ penta ( methylene ) phosphonic acid ( dtmp ), to form a bone - seeking complex . purification of the final product can be performed using ion exchange procedures and sterile filtration . as described above , separation of ac - 226 from irradiated ra - 226 targets can be performed using known procedures of ion exchange or extraction chromatography . for the direct use of ac - 226 in radiotherapy , purified ac - 226 will be dissolved in a first step in dilute acid , preferentially hydrochloric or nitric acid . for the use of ac - 226 in targeted radiotherapy , the radionuclide is mixed with a buffered solution of a chelated carrier molecule ( targeting moiety ) in e . g . sodium acetate buffer and incubated for an appropriate time . purification of the ac - 226 - radioconjugates can be performed using size exclusion chromatography or ion exchange procedures and sterile filtration . representative conditions for the chelation coupling are given here : to 150 μl of ac - 226 in 0 . 1 m hcl , a mixture of 40 μl of 2 m sodium acetate buffer and 10 μl of 10 % ascorbic acid solution as radioprotectant is added to adjust the ph to a value of 5 - 6 . following addition of 100 μg of heha - chelated - antibody in buffered solution , the solution is incubated for 90 minutes . subsequently 10 μl of a solution containing 1 . 5 mg / ml dtpa are added to quench the chelation reaction . immediately after dtpa - addition , the radioconjugates are purified by size - exclusion chromatography and passed through a sterile filter . preferred conditions for a 2 - step chelation coupling of ac - 226 are given here : 226 ac ( in 25 μl 0 . 2 mol / l hcl ) is incubated with i - ascorbic acid ( 150 g / l , 20 μl ), 2 -( p - isothiocyanatobenzyl )- 1 , 4 , 7 , 10 - tetraazacyclododecane - 1 , 4 , 7 , 10 - tetraacetic acid ( dota - ncs ) ( 10 g / l , 50 μl ), and tetramethylammonium acetate ( 2 mol / l , 50 μl ) to facilitate incorporation of 226 ac into dota . the reaction is allowed to continue for 30 min at 60 ° c . ( ph 5 . 0 ). for conjugation of 226 ac - dota to the antibody ( the second - step reaction ), another 20 μl of ascorbic acid are added before adding 1 mg of antibody ( 200 μl ). the ph is adjusted with carbonate / bicarbonate buffer ( 1 mol / l , 100 μl ) to 9 . 0 and incubation is for 30 min at 37 ° c . subsequently free 226 ac along with other metals is absorbed with 20 μl 10 mmol / l diethylenetriaminepentaacetic acid ( dtpa ) and the unconjugated 226 ac is separated from the 226 ac - radioconjugates by pd10 size exclusion ( bio - rad ) using 1 % human serum albumin in 0 . 9 % saline as eluent . quality control of the final product can include thin - layer chromatography to determine radiopurity , a cell - based binding assay to measure immunoreactivity of the antibody vehicle , limulus amebocyte lysate testing to determine pyrogen content , and microbiologic culture in fluid thioglycollate of soybean - casein digest medium to verify sterility . for the use of ac - 226 in pre - targeted radiotherapy , the radionuclide is mixed with a buffered solution of chelated biotin or another suitable carrier molecule and incubated for an appropriate time . purification of the ac - 226 - radioconjugates can be performed using ion exchange procedures and sterile filtration . representative conditions for chelation coupling are given here . to a solution containing ac - 226 in 0 . 2 m ammonium acetate , ph 5 . 0 , containing approximately 10 mg / ml of ascorbic acid as a radioprotectant , 2 μg of heha - biotin in 1 μl of 0 . 2 m ammonium acetate , ph 5 . 0 , are added . the reaction mixture is incubated for 90 min , after which 10 μl of a solution containing 1 . 5 mg / ml dtpa , ph 6 . 0 , is added . immediately after dtpa - addition , the biotin radioconjugates are purified and passed through a sterile filter . twenty microliters to 100 μl carrier - free ac - 226 in 0 . 05 m hcl is diluted with 2 m ammonium acetate , ph 5 , to a total volume of 0 . 25 ml , and 1 mg dota - biotin is added . the solution is heated for 30 minutes at 80 ° c . followed by the addition of 25 μl 100 mm dtpa to chelate any unbound radioisotope . radio - chemical purity is determined by c 18 reverse - phase gradient high - performance liquid chromatography ( hplc ) with flow - through gamma detection . for the use of ac - 226 for bone - targeting , the solution containing ac - 226 is subsequently mixed with a solution of an appropriate complexing agent to form bone - seeking complexes . suitable bone - seeking chelating and / or complexing molecules include , but are not limited to , phosphonic acid complexants , e . g . 1 , 4 , 7 , 10 tetraazacyclododecane n , n ′, n ″, n ″′ 1 , 4 , 7 , 10 - tetra ( methylene ) phosphonic acid ( dotmp ) as described in [ ref . 8 ]. if required , purification of the final product can be performed using ion exchange procedures and sterile filtration . 4 . chelating and complexing molecules for binding of u - 230 , ac - 226 and th - 226 the coupling of th - 226 , ac - 226 and / or u - 230 to the targeting moiety can be done in any suitable way , as long as the target specificity of the targeting moiety is not substantially reduced . suitable complexing or chelating molecules that can be used to bind th - 226 , ac - 226 and / or u - 230 to targeting moieties such as biological carrier molecules ( e . g . monoclonal antibodies , humanized antibodies , antibody fragments or peptides ) or carrier molecules for pre - targeted radiotherapy ( e . g . biotin ) are widely described in the literature . when u - 230 is used in targeted or pre - targeted radiotherapy , preferentially a chelating molecule ( agent ) should be used that binds uranium as well as its daughter nuclide thorium in a stable manner , in order to minimise the dislocation of th - 226 from the target cell following its formation through the decay of u - 230 in situ . possible chelating molecules that can be used to bind uranium and thorium include multidentate ligands containing catecholate , catecholamide or hydroxy - pyridinone units as described in [ ref . 7 ], e . g . 5 - lio ( me - 3 , 2 - hopo ), 5 - licam ( s ), 3 , 4 , 3 - li ( 1 , 2 - hopo ) as described in [ ref . 6 ] and 5 - li ( me - 3 , 2 - hopo ) [ ref . 7 ]. analogously , when ac - 226 is used in targeted or pre - targeted radiotherapy , preferentially a chelating molecule should be used that binds actinium as well as its daughter nuclide thorium in a stable manner , in order to minimise the dislocation of th - 226 from the target cell following its formation through the decay of ac - 226 in situ . dtpa ( diethylenetriaminepentaacetic acid ) and its derivatives ( e . g . benzyl - dtpa , mx - dtpa ( tiuxetan ), cyclohexyl - dtpa ), preferentially for chelation of thorium ; dota ( 1 , 4 , 7 , 10 - tetraazacyclododecane - n , n ′, n ″, n ″′- tetraacetic acid ) and its derivatives , preferentially for chelation of actinium ; heha ( 1 , 4 , 7 , 10 , 13 , 16 - hexaazacyclooctadecane - n , n ′, n ″, n ′″, n ″″, n ″″′- hexaacetic acid ) and its derivatives , preferentially for chelation of actinium and thorium ; ohec ( octaazacyclohexacosane - 1 , 4 , 7 , 10 , 14 , 17 , 20 , 23 - octaacetate ) and its derivatives , preferentially for chelation of actinium and thorium ; multidentate ligands containing catecholate , catecholamide or hydroxypyridinone units as described in [ ref . 7 ], e . g . 5 - lio ( me - 3 , 2 - hopo ), 5 - licam ( s ), 3 , 4 , 3 - li ( 1 , 2 - hopo ) as described in [ ref . 6 ] and 5 - li ( me - 3 , 2 - hopo ) [ ref . 7 ]; calixarene systems , crown ethers ; molecules that are studied as sequestering agents for tri -, tetra - and hexavalent actinides as described in [ ref . 7 ]. for application in the present invention , the binding of actinium and / or thorium to antibody constructs chelated with heha and derivatives of dtpa , respectively , and their stability in human blood serum has been studied . monoclonal antibodies chelated with benzyl - dtpa and cyclohexyl - dtpa , respectively , were coupled to th - 227 , used as chemical analog of th - 226 . in a typical experiment , 0 . 5 ml of th - benzyl - dtpa - antibody radioconjugate or th - cyclohexyl - dtpa - antibody radioconjugate , respectively , were added to 1 . 0 ml of human blood serum at 37 ° c . and kept under 5 % co 2 - atmosphere . at appropriate time points the fractions of thorium bound to the antibody and released from the antibody , respectively , were analysed by thin layer liquid chromatography using 0 . 05 m edta as solvent . as summarized in table 3 , the th - benzyl - dtpa - antibody radioconjugate ( denoted rc1 ) as well as the th - cyclohexyl - dtpa - antibody radioconjugate ( denoted rc2 ) showed excellent stability in human blood serum . after 5 hours incubation in human blood serum , only negligible fractions of thorium were released from the antibody construct . considering the half - life of th - 226 ( t 1 / 2 = 31 min ), the data show that thorium will remain bound to the antibody - construct for a time period exceeding 10 half - lives , resulting in virtually complete decay of th - 226 while bound to the antibody . therefore derivatives of dtpa are recommended as excellent chelators for the coupling ( or binding ) of thorium to targeting moieties . in an analogous experiment , monoclonal antibodies chelated with heha were labelled using th - 227 as chemical analog of th - 226 . in a typical experiment , 0 . 5 ml of th - heha - antibody construct were added to 1 . 0 ml of human blood serum at 37 ° c . and kept under 5 % co 2 - atmosphere . at appropriate time points the fractions of thorium bound to the antibody and released from the antibody , respectively , were analysed by thin layer liquid chromatography using 0 . 05 m edta as solvent . as summarized in table 4 , the th - heha - antibody radioconjugate ( denoted rc3 ) showed moderate stability in human blood serum . after 5 hours incubation in human blood serum , approx . 30 % of thorium were released from the antibody construct . considering the half - life of th - 226 ( t 1 / 2 = 31 min ), the data show that approx . 70 % of thorium will remain bound to the antibody - construct for a time period exceeding 10 half - lives . therefore heha may be used as chelator for linking of thorium to targeting moieties . to study the stability of actinium radioimmunoconjugates in human blood serum , monoclonal antibodies chelated with heha were labelled using ac - 225 as chemical analog of ac - 226 . in a typical experiment , 0 . 5 ml of ac - heha - antibody radioconjugates were added to 1 . 0 ml of human blood serum at 37 ° c . and kept under 5 % co 2 - atmosphere . at appropriate time points the fractions of actinium bound to the antibody and released from the antibody , respectively , were analysed by thin layer liquid chromatography using 0 . 05 m edta as solvent . as summarized in table 5 , the ac - heha - antibody radioconjugate ( denoted rc4 ) showed sufficient stability in human blood serum . after 145 hours incubation in human blood serum , corresponding to 5 half - lives of ac - 226 , only approx . 20 % of total actinium activity were released from the radioconjugate . the use of heha for the linking of ac - 225 to targeting moieties is widely described in the literature and is proposed as an advantageous chelating agent of ac - 226 in the frame of this invention . hence , it has been found that heha binds actinium and thorium in a relatively stable manner . accordingly , the present invention also proposes the use of heha to bind ac - 226 to targeting moieties , since it is of particular advantage in order to minimise dislocation of the in situ produced th - 226 from the target site . 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