EP0757694A1 - Thioether zur verwendung in der herstellung bifunktioneller chelatisierungsmittel für therapeutische radiopharmazeutika - Google Patents

Thioether zur verwendung in der herstellung bifunktioneller chelatisierungsmittel für therapeutische radiopharmazeutika

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Publication number
EP0757694A1
EP0757694A1 EP95917659A EP95917659A EP0757694A1 EP 0757694 A1 EP0757694 A1 EP 0757694A1 EP 95917659 A EP95917659 A EP 95917659A EP 95917659 A EP95917659 A EP 95917659A EP 0757694 A1 EP0757694 A1 EP 0757694A1
Authority
EP
European Patent Office
Prior art keywords
ligand
rhodium
group
complexes
iii
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP95917659A
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English (en)
French (fr)
Other versions
EP0757694A4 (de
Inventor
Meera Venkatesh
Silvia Jurisson
Elmer Schlemper
Alan R. Ketring
Wynn A. Volkert
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University of Missouri System
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University of Missouri System
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Filing date
Publication date
Application filed by University of Missouri System filed Critical University of Missouri System
Publication of EP0757694A1 publication Critical patent/EP0757694A1/de
Publication of EP0757694A4 publication Critical patent/EP0757694A4/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D341/00—Heterocyclic compounds containing rings having three or more sulfur atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0073—Rhodium compounds
    • C07F15/008—Rhodium compounds without a metal-carbon linkage

Definitions

  • the present invention relates to compounds which chelate radioactive atoms and have chemical properties which can be used in designing radiotherapeutic agents. More specifically, the present invention relates to a chelate which can complex preferably with rhodium-105, a radioactive form of rhodium for use as a radiotherapeutic.
  • Radiotherapy using "non-sealed sources” by way of radiolabeled pharmaceuticals has been employed for several decades for cancer treatment [1,2].
  • There is a great deal of interest in developing new agents due to the emergence of more sophisticated biomolecular carriers that have high affinity and high specificity for in vivo targeting of tumors.
  • Several types of agents are being developed and investigated at a rapid pace, including monoclonal antibodies (MAbs) , antibody fragments or Single Chain Antibodies (SCAs) and peptide-based and non- peptide receptor-avid molecules [3-7].
  • Radiolabeling of these types of molecules with gamma- or positron-emitting radionuclides have produced effective agents for scintigraphic and PET imaging for diagnostic utility in cancer patients [8-10] .
  • Development of radiotherapeutic agents is also occurring, however, at a much slower rate and is more problematic.
  • the choice of the particle emitting radionuclides for labeling of biomolecules for specific applications is not trivial [11-13].
  • Many factors must be considered when selecting the appropriate therapeutic radionuclide, including particle energies, matching of half-life with pharmaco inetics, availability, specific activity, suitability of an appropriate chelation system for coupling the radionuclide to the vector, _Ln vivo stability, etc. [13,14].
  • Radiolabeled drugs target tumor cell populations that have a limited number of binding sites or receptors which in turn limits the quantity (i.e., usually greater than 100 nmoles and often less than 20 nmoles) of the pharmaceutical that can be administered [15,16].
  • the specific activity of these radiolabeled drugs must usually be high (i.e., > 100 m (i/nmole) [15,16].
  • the most attractive and perhaps the only functional radionuclides that can be used with these types of pharmaceuticals are those readily available in high specific activities. Relatively few beta-particle emitting radionuclides can be produced in sufficient quantities for treatment of very large numbers of patients [11-13].
  • One of these radionuclides is rhodium-105 ( 105 Rh) [13,17].
  • the moderate energy beta particles [E ⁇ - (max) 560 keV (70%) and 250 keV (30%)] emitted by 105 Rh make it attractive for therapy while the 306 and 319 keV gamma rays emitted in relatively low abundance (5% and 19% respectively) could be used for imaging in conjunction with therapy applications, if desired.
  • the half-life of 105 Rh is 1.44 d which could be a good match for the pharmacokinetics of receptor binding agents or MAb fragments. It can be readily produced in large quantities "indirectly" in a no-carrier-added (NCA) form by bombardment of w Ru (>99% enriched) to produce 105 Ru which decays (t ⁇ - 4.4 hr) to 105 Rh.
  • the 105 Rh can be separated from the Ru to obtain the high specific activity 105 Rh [18]. It is also possible to obtain samples containing high activities (i.e., 10 3 curies) of 105 Rh as a fission product, if required [17].
  • Therapeutic agents have been primarily labeled with beta-particle emitting radionuclides. Most of the promising radionuclides are produced in nuclear reactors, however, some are accelerator produced [11-13].
  • Several different chelating structures have been employed to maintain the association of these beta emitters with the drug [19-23]. Many of these structures are not sufficiently stable and most, if not all, do not provide appropriate routes or rates of clearance of radioactivity from non-target tissues [23,24].
  • Bifunctional chelating agents have been used to form stable metal complexes that were designed to minimize in vivo release of the metallic radionuclide from the radiopharmaceutical.
  • diethylenetriaminepentaacetic acid DTPA
  • DTPA diethylenetriaminepentaacetic acid
  • monoclonal antibodies by one of its five carboxyl groups resulted in unacceptable in vivo stability with a variety of radionuclides [14].
  • Linking of this compound by a side group attached to one of the carbon atoms on an ethylene bridging group provides improved stability in vitro and in vivo.
  • the stability characteristics of this chelate and its analogues with all radioactive metals are not ideal resulting in poor clearance of activity from certain non-target organs.
  • Rh (III) forms a variety of complexes that are chemically inert under physiologic conditions [25] makes 105 Rh (III) particularly attractive for formulating new 105 Rh- labeled bifunctional chelating agents to form new therapeutic radiopharmaceuticals.
  • 105 Rh (III) particularly attractive for formulating new 105 Rh- labeled bifunctional chelating agents to form new therapeutic radiopharmaceuticals.
  • the formation of desirable Rh (III) chelates in aqueous media usually requires rather harsh conditions (e.g. refluxing for greater than two hours) [26-29].
  • polymerized forms of Rh are often produced, even with a large excess of the ligand [30,31].
  • Complexation of Rh with a variety of thioether compounds has been reported recently [28- 32].
  • Rh (III) considered a moderately soft acid, will usually form stable complexes with ligands containing "soft" donor atoms (e.g., thioethers) [32,33].
  • "soft" donor atoms e.g., thioethers
  • Blake et al., (1989) [32] showed that 1,5,9,13-tetrathiacyclohexadecane (16-ane-S 4 ) forms trans Rh(III)Cl- complexes with Rh(III) chloride.
  • the ability of thioether compounds to complex Rh(III) in high yields at low ligand concentrations has not been investigated. Unfortunately, almost all metal chelates with high thermodynamic stabilities are not sufficiently stable in vivo and will not form in high yields using low quantities of ligand.
  • a compound consisting essentially of a multidentate ligand including at least two thioether groups for being complexed to rhodium- 105.
  • the present invention further provides stable complexes of Rhodium-105 with 16-ane-S 4 -diol, 14- ane-NS- and 14-ane-N-S- ligand.
  • Figure 1 is a radiochromatogram of electrophoresis analysis of
  • Rh-l6-ane-S 4 -diol at different temperatures as a function of heating time, studies being performed using 10 ⁇ g 16-ane-S 4 -diol in 0.5 ml solutions at pH 4 containing 15% ethanol;
  • Figure 3 shows the stability of 105 Rh-l6- ane-S 4 -diol at pH 7.4, 8.5 and in human serum at pH 7.4-7.8 for greater than 4 days, samples being maintained at (a) pH 7.4 in .09% saline (N. saline) at room temperature (RT) using 0.05M sodium phosphate; (b) pH 8.5 in N. saline at RT using 0.1M sodium bicarbonate and (c) pH 7.4-7.8 in human serum at 37 * C;
  • Figure 4 is a radiochromatogram of electrophoreses of:
  • Rh-l4-ane-NS 3 as a function of temperature, 12 ⁇ g
  • the present invention provides a compound consisting essentially of a multidentate ligand including at least two thioether groups for being complexed to rhodium-105. That is, the compound can contain an 105 Rh core and a multidentate ligand containing two or more thioether (TE) groups for bonding to the metal.
  • TE thioether
  • the resulting 105 Rh-TE complexes have high in vitro and in vivo stability and are formed using low quantities of the ligand (i.e., ⁇ 50 nmoles).
  • the TE containing ligand is complexed to 105 Rh to form a chelate where the metal to ligand ratio is 1:1.
  • the method of complexation permits the formation of the 105 Rh-chelate in a one step, high yield reaction (exemplified in the Experimental Section) , especially with 105 Rh- synthons that are currently available or can be made commercially available.
  • the 105 Rh-chelates are produced in high yields (i.e.
  • 105 Rh chelates required more severe conditions (e.g. , refluxing for greater than two hours) and the use of larger quantities of the complexing ligands. Synthesis of 105 Rh chelates under these conditions will normally destroy the specificity or binding affinity of sensitive biomolecules and produce 105 Rh-compounds with specific activities that are usually too low for use as radiopharmaceuticals.
  • the 105 Rh chelates made in accordance with the present invention have been found to be stable in aqueous solutions and in human serum at 37"C.
  • chelates are also stable over a wide pH range (i.e., pH 1-10). This high stability is critical with regard to permitting localization of the compound in areas of the body having different pH's as well as being stable through different administration routes. More specifically, the thioether (TE) containing multidentate ligands used for complexing
  • 105 Rh can be characterized by the following formulas:
  • X's are or contain "donor" atoms that will complex Rh-105 (i.e., S, 0, or N) .
  • R 1 , R 2 , R 3 , and R 4 are all the same or different and are selected from the group consisting of -(CH-)--, -(CH 2 ) 3 -, -CH-CH (C 3 CH--, -(CH-) 4 -, -CH 2 CH(R 5 )-,
  • R 5 is -H, or any side chain containing groups commonly used for linking (e.g.,-OH, NH 2 , COOH -NCS, activated ester) .
  • R 5 also can be selected from the group consisting of -OCH-, -OC 2 H 5 and groups for attaching a linking group used to modify lipophilicity for conjugation of the uncomplexed ligand or the ligand chelated to 105 Rh to a biomolecular targeting agent and R 1 " 4 can also contain another coordinating atom, e.g., R 6 -X 4 -R 6 , wherein R 6 is -(CH 2 ) 2 -, -(CH-)--, -CH-CH(CH)-CH--, -(CH 2 CH(R 5 )CH 2 )-, -CH(R 5 )CH-CH--, -CH-CH(CH-R 5 )CH 2 ⁇ , wherein R 5 is -OH, NH 2 , COOH.
  • X 1'4 is an atom or group containing S, 0 or N donor atoms that can also coordinate 105 Rh(III) , wherein X 1 , X 2 , X 3 and X 4 are all the same or different in which one of the X's is an -S- and the others are -S, -0-, NH, NR 7 , wherein R 7 is H, -CH 3 or a group attached to the N- atom to alter lipophilicity or to link the uncomplexed ligand or the "preformed" 105 Rh-chelate to the biomolecular targeting agent.
  • the ligand may be uncomplexed; that is, not complexed to the Rhodiu -
  • the ligand may be complexed to the Rhodium and referred to as "precomplexed".
  • precomplexed either an uncomplexed or precomplexed ligand can be linked to a receptor avid molecule.
  • Several chemical methods for conjugating ligand or metal chelates to biomolecules have been well described in the literature [36,37] and one or more of these methods will be used to link the uncomplexed TE ligands or 105 Rh-TE complexes to the receptor avid biomolecular targeting molecules. These include the use of acid anhydrides, aldehydes, arylisothiocyantes, activated esters or N-hydroxysuccinimides [36, 37].
  • the ligands can also be linear, open chain-ligands, containing at least one thioether group.
  • the compounds are exemplified by the following formula:
  • R 1 , R 2 and R 3 are all the same or different and are selected from the groups consisting of -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH 2 CH(CH) 3 CH 2 -, -(CH 2 ) 4 -,
  • R 4 and R 5 can be the same or different and can be H or an alkyl group or a linking group containing functional groups such as -OH, NH 2 , COOH. -OCH 3 , -OC 2 H 2 and other functional groups for attaching a linking group used to modify lipophilicity for conjugation of the uncomplexed ligand or the ligand (chelated or not to 105 Rh) to the bimolecular targeting agent.
  • X 1*4 is an atom or group that can also coordinate 105 Rh(III) .
  • X 1 , X 2 , X 3 , and X 4 are all the same or different when at least one X is a S-atom and the remaining are selected from the group consists of -S-, -0-, -SH, NH and NR 7 .
  • R 7 is selected from the group consisting of H, -CH 3 and a group attached to the N- atom to alter lipophilicity or to link the uncomplexed ligand or the ligand complexed to 105 RH to the biomolecular targeting agent.
  • the above formulas characterize the present invention as providing capabilities for ligand modifications in order to tailor the ligands, that when chelated to 105 Rh, can be designed to optimize in vivo binding and pharmacokinetic properties for specific localization on target tissues (i.e., cancerous cells or tumors) .
  • target tissues i.e., cancerous cells or tumors
  • the uncomplexed ligand or corresponding 105 Rh-chelate can be conjugated to peptides and other receptor avid molecules (targeting molecules) such as antibodies and antibody fragments by using side chains previously used for conjugation to bioactive molecules [36,37].
  • Conjugation reactions can involve reactive groups such as benzyl isothiocyanate, bromoacetamide, N-hydroxy-succinimides, activated esters and aldehydes (15) .
  • Charged groups can be added to either the C- backbone or other sites (i.e., N-atoms) to increase the hydrophilic character of the resulting chelate.
  • non-polar groups e.g. , alkyl, alkoxy, etc.
  • non-polar groups e.g. , alkyl, alkoxy, etc.
  • one of the terminal groups on the linear ligand is a thiol group
  • a neutral- lipophilic 05 Rh chelate should be formed.
  • thioether ligands used in accordance with the present inventions were purchased commercially or could be made by methods similar to those outlined in the literature [34,35]. Attachment of side chains to functionalizable atoms on the ligand backbone (e.g., N-atoms) or attached to the ligand backbone (e.g., -OH, amines or carboxyl groups) are performed by standard methods. For example, the available 14-ane-NS 3 macrocyclic ligand shown below is derivatized by reaction of an alkyl halide with the lone ring N-atom to produce a variety of thioether derivatives.
  • the commercially available 16- ane-S 4 diol (1,5,9,13 tetrathiacyclo-hexane-3,11- diol) can be modified as shown below for attaching a single side chain (R) to the ligand.
  • the R group can then be used for conjugation to bioactive molecules [36,37].
  • radiopharmaceutical it is meant that the chelate linked to a targeting molecule can be used to localize sufficient levels of 105 Rh at a site to provide radiotherapeutic properties.
  • the chelate including the 105 Rh is bound to a targeting molecule, such as a peptide, antibody or other receptor avid molecule directed towards a specific antigen or other receptor on a target cell.
  • a targeting molecule such as a peptide, antibody or other receptor avid molecule directed towards a specific antigen or other receptor on a target cell.
  • Such compounds formed in high specific activities i.e., greater than 100 curies/nmole
  • sufficient stability in accordance with the present invention can be injected, circulate through the patient's system, and bind at target tissue to then provide radiotherapy at that site.
  • the preferred compounds of the present invention contain two or more thioether groups that form high specific activity complexes with the rhodium-105 at high yields, as demonstrated below.
  • the tetrathiamacrocycle (16-ane-S 4 diol) which is an example of the present invention as indicated above, chelates rhodium-105 to form a single species at low ligand concentrations permitting production of high specific activity chelates.
  • the formed rhodium-105-16-ane-S 4 -diol chelate is stable for up to and greater than four days at physiological pH.
  • This model S 4 ligand used in the experimental studies below includes two hydroxyl groups which can be used for linking either the macrocycle alone or the rhodium-105 chelate to biomolecules. Hence, there is significant potential for S 4 ligands and analogs thereof for use in formulating new rhodium- 105 therapeutic radiopharmaceuticals.
  • the advantages of the present invention are numerous.
  • the compound made in accordance with the present invention forms a stable, well defined, single species.
  • the rhodium-105(III)-l6-ane-S 4 -diol chelate is formed in high yield under relatively mild conditions (i.e., 65*C for 60-90 minutes). Since these mild conditions will not result in significant 105 Rh(III) complexation with other groups on proteins, such as amines, carboxyls, or hydroxyls etc. or most other molecules, the 105 Rh(III) is able to selectively chelate to S 4 moieties already linked to biomolecular targeting molecules.
  • the resulting 105 Rh-pharmaceutical can be used to selectively localize the 105 Rh on target cells.
  • substitution of N-atoms for the thioether groups also results in high 105 Rh-complexation yields.
  • SUBSTITUTE SHEET(RULE 26 biomolecular targeting molecules include the use of acid anhydrides, aldehydes, arylisothyiocyantes, activated esters or N-hydroxysuccinimides [14].
  • the 105 Rh-chloride reagent contains a mixture of 105 Rh (III) species, presumed to include 105 RhCl 3 (H 2 O) 3 , 105 RhCl 4 (H 2 O) 2 ' , 105 RhCl 5 (H 2 O) '2 and 105 RhCl 6 "3 [38,40]. Electrophoresis of this reagent typically demonstrates a mixture primarily composed of three different anionic 105 Rh-species, presumably tetra, penta- any hexachloro- 105 Rh(III) anions.
  • the 105 Rh-complex with 16-ane-S 4 -diol is cationic and is a single species as determined by electrophoresis performed at 300 V for 1 hour on paper strips saturated with 0.075M sodium phosphate buffer at pH 4.5 ( Figure 1).
  • Silica-TLC also was used to routinely measure complex yield.
  • the silica-TLC plates were developed with 0.9% aqueous NaCl (i.e., N saline), on which the uncomplexed 05 Rh-chloride reagent has a R f of 0.9-1.0 while the R f of the 105 Rh-16-ane-S 4 -diol is 0.05-0.10.
  • the 105 Rh-16-ane-S 4 -diol is assigned to be [ 105 Rh(III) (16-ane-S 4 -diol)Cl 2 ] + as shown below:
  • SUBSTITUTE SHEET (RULE 2® [Rh(III)16-ane-S 4 -diol)Cl 2 ] + was prepared by a method similar to that described by Blake, et al. [32] for a similar S 4 -macrocycles.
  • the PF 6 " salt of this chelate was crystallized and fully characterized by NMR, UV-spectroscopy, elemental analysis and X-ray crystallography.
  • the 105 Rh-14-ane-NS 3 chelate has the same electrophoretic migration distance as 105 Rh-l6-ane-S 4 -diol, indicating the two chelates have the same overall charge (i.e., +1).
  • 105 Rh-l4-ane-NS 3 was also shown to be stable in aqueous solutions for greater than 4 days.
  • EXAMPLE 3 105 Rh-complexation with 14-ane-N 2 S 2 ⁇
  • Rh-complexation yields can be achieved using a ligand with two thioether group and two amine functionalities.
  • the above experimental results demonstrate that the ligands made in accordance with the present invention that contain at least two thioether groups that form complexes with rhodium-105 can be made in high yields.
  • the specific ligands examined form a single species on complexation to Rhodium-105, in low concentrations,
  • the ligands are stable for greater than four days at physiological pH.
  • the _ligand used having at two hydroxyl groups attached to the ligand backbone can be easily used for linking the macrocycle or rhodium chelate acrocycle to biomolecules as known in the art. Accordingly, there is great potential for the present invention and analogs thereof in formulating therapeutic pharmaceuticals.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP95917659A 1994-04-29 1995-04-25 Thioether zur verwendung in der herstellung bifunktioneller chelatisierungsmittel für therapeutische radiopharmazeutika Withdrawn EP0757694A4 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US23635394A 1994-04-29 1994-04-29
US236353 1994-04-29
PCT/US1995/005045 WO1995029925A1 (en) 1994-04-29 1995-04-25 Thioether compounds for use in preparing bifunctional chelating agents for therapeutic radiopharmaceuticals

Publications (2)

Publication Number Publication Date
EP0757694A1 true EP0757694A1 (de) 1997-02-12
EP0757694A4 EP0757694A4 (de) 1998-05-06

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EP95917659A Withdrawn EP0757694A4 (de) 1994-04-29 1995-04-25 Thioether zur verwendung in der herstellung bifunktioneller chelatisierungsmittel für therapeutische radiopharmazeutika

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EP (1) EP0757694A4 (de)
JP (1) JPH09512796A (de)
AU (1) AU2363495A (de)
CA (1) CA2188565A1 (de)
WO (1) WO1995029925A1 (de)
ZA (1) ZA953448B (de)

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JP4480245B2 (ja) * 2000-03-13 2010-06-16 株式会社コスモ総合研究所 環状アニリン硫化物とその製造方法
MA38571B1 (fr) 2013-05-13 2018-10-31 Vision Global Holdings Ltd Composition pharmaceutique comprenant un agent thérapeutique à base d'hémoglobine modifiée pour un traitement de ciblage du cancer et imagerie diagnostique

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US5175343A (en) * 1985-01-14 1992-12-29 Neorx Corporation Metal radionuclide labeled proteins for diagnosis and therapy
US4994560A (en) * 1987-06-24 1991-02-19 The Dow Chemical Company Functionalized polyamine chelants and radioactive rhodium complexes thereof for conjugation to antibodies
US4782013A (en) * 1987-07-23 1988-11-01 Eastman Kodak Company Photographic element containing a macrocyclic ether compound
GB9007039D0 (en) * 1990-03-29 1990-05-30 Isis Innovation Complexes of thioethers
FR2662159B1 (fr) * 1990-05-15 1994-03-11 Matieres Nucleaires Cie Gle Nouveaux ligands thio-ethers et leur utilisation pour separer le palladium de solutions aqueuses, en particulier de soludtions nitriques de dissolution d'elements combustibles nucleaires irradies.

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AU2363495A (en) 1995-11-29
CA2188565A1 (en) 1995-11-09
EP0757694A4 (de) 1998-05-06
JPH09512796A (ja) 1997-12-22
WO1995029925A1 (en) 1995-11-09
ZA953448B (en) 1996-01-12

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