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WO1998024480A1 - Analogues radio-iodes d'ethers phospholipidiques et leurs procedes d'utilisation - Google Patents

Analogues radio-iodes d'ethers phospholipidiques et leurs procedes d'utilisation Download PDF

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Publication number
WO1998024480A1
WO1998024480A1 PCT/US1996/019352 US9619352W WO9824480A1 WO 1998024480 A1 WO1998024480 A1 WO 1998024480A1 US 9619352 W US9619352 W US 9619352W WO 9824480 A1 WO9824480 A1 WO 9824480A1
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WIPO (PCT)
Prior art keywords
compound
iodophenyl
tumor
iodine
phosphocholine
Prior art date
Application number
PCT/US1996/019352
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English (en)
Inventor
Raymond E. Counsell
Marc A. Longino
Anatoly N. Pinchuk
Mark A. Rampy
Jamey P. Weichert
Original Assignee
The Regents Of The University Of Michigan
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by The Regents Of The University Of Michigan filed Critical The Regents Of The University Of Michigan
Priority to CA002276284A priority Critical patent/CA2276284C/fr
Priority to PCT/US1996/019352 priority patent/WO1998024480A1/fr
Priority to US09/319,406 priority patent/US6255519B1/en
Publication of WO1998024480A1 publication Critical patent/WO1998024480A1/fr
Priority to US09/898,178 priority patent/US6417384B1/en

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    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/094—Esters of phosphoric acids with arylalkanols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0404—Lipids, e.g. triglycerides; Polycationic carriers
    • A61K51/0408—Phospholipids
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the present invention relates generally to the field of radiopharmaceuticals and biological probes, and more specifically to radiolabelled analogs of phospholipid ethers useful in cancer diagnosis and treatment.
  • CT computed tomography
  • MRJ magnetic resonance imaging
  • PET positron emission tomography
  • SPECT single photon emission tomography
  • the success of these nuclear imaging techniques depends in large part on the selective uptake and detection of appropriate radiopharmaceuticals. Selective uptake, in turn, depends upon the development of radiopharmaceuticals with a high degree of specificity for the target tissue.
  • the tumor-localizing agents developed thus far for oncological applications have had only limited application.
  • 67 Ga gallium citrate was originally identified for its ability to accumulate in tumor tissue.
  • 67 Ga gallium citrate is taken up by a variety of other non-tumorous lesions as well, including inflammatory lesions. and unacceptable amounts of radioactivity can also accumulate in liver and spleen tissue.
  • the rapid buildup of a radiopharmaceutical in these organs can seriously interfere with the imaging of nearby lesions, and also negatively impacts the dosage that can safely be given to a patient.
  • An alternative approach has been to develop radiolabelled monoclonal antibodies
  • Mabs directed to tumor-specific antigens.
  • these monoclonal antibodies are specific only to the particular tumor tissue for which they have been produced, and therefore will not localize generally in neoplastic tissue.
  • the use of Mabs for diagnostic imaging has lead to additional problems, including varying degrees of antigen expression, low tumor uptake, non-specific binding and adverse immunogenic reactions.
  • radiopharmaceuticals which exhibit a rapid clearance from non-target tissues as well as an extended half-life in the blood plasma, while still retaining its specificity and avidity for neoplastic tissue.
  • Such an agent should not only assist in the non-invasive imaging of primary tumors and metastases. but should also provide a potential cytotoxic agent for site-specific eradication of the tumor tissue.
  • the present invention solves the problems present in the prior art through the provision of improved radiolabelled phospholipid ether analogs of naturally-occurring phospholipid ether compounds, having the general Formula I:
  • X is a radioactive isotope and n is an integer between 16 and 30.
  • X is a radioactive isotope of iodine, preferably selected from the group comprising 123 I, l25 I, and 13I I. It is further contemplated that X can be substituted at the ortho, meta or para position on the aromatic ring. In a preferred embodiment, the radioactive isotope is substituted at the para position.
  • Y is selected from the group comprising H, OH, COOH, ⁇ • . and OR, and Z is
  • OCR selected from the group comprising NH 2 , NR 2 , and NR 3 , wherein R is an alkyl or aralkyl substituent.
  • the improved compound is l -0[ 18-(p-iodophenyl)octadecyl]-l ,3-propanediol-3-phosphocholine.
  • the improved compound is l -0-[18-(p-Iodophenyl)octadecyl]-2-0-methyl-r ⁇ c-glycero-3-phosphocholine:
  • radiolabelled aralkyl side chain may be substituted directly onto the alkyl phosphocholine moiety in accordance with general Formula II:
  • X is a radioactive isotope substituted at the ortho. meta or para position, preferably of iodine
  • n is an integer from 16 to 30
  • Y is selected from the group comprising NH 2 , NR : and NR 3 , wherein R is an alkyl or aralkyl substituent.
  • the improved compound is 18-(p-iodophenyl)octadecyl phosphocholine.
  • Figure 1 is an illustrative preparatory scheme for 18-(p-iodophenyl)octadecanol
  • Figure 2 is an illustrative preparatory scheme for 18-(p-iodophenyl)octadecyl phosphocholine;
  • Figure 3 is an illustrative preparatory scheme for l-0-[18-(p-iodophenyl)octadecyl]-
  • Figure 4 is an illustrative preparatory scheme for l -0-[18-(p-iodophenyl)octadecyl]-2- O-methyl-r ⁇ c-glycero-3-phosphocholine;
  • Figures 5A-5C provide the chemical structures of the alkyl chain length analogs ⁇ 2-(p- iodophenyl)dodecyl phosphocholine ( Figure 5 A), 15-( -iodophenyl)pentadecyl phosphocholine
  • Figure 6 provides a line graph illustrating the blood clearance profile of ⁇ 2- ⁇ p- iodophenyl)dodecyl phosphocholine (C-12), 15-(/?-iodophenyl)pentadecyl phosphocholine (C- 15) and 18-(/ iodophenyl)dodecylphosphocholine (C-18) in rats bearing Walker-256 tumors;
  • Figures 7A-7C provide the chemical structures of the alkyl chain length analogs l2-(p- iodophenyl)dodecyl phosphocholine ( Figure 7A), 18-(/ iodophenyl)octadecyl phosphocholine ( Figure 7B). and l-(3-[18-(p-iodophenyl)octadecyl]-l ,3-propanediol-3-phosphocholine used in biodistribution studies with rats bearing Dunning (MATLyLu) prostate tumors;
  • Figures 8A-bC are depictions of whole-body gamma-camera scintigraphy scans of
  • the present invention represents a significant improvement of the radiolabelled phospholipid ether analogs previously described in the prior art, providing a series of radiopharmaceutical compounds exhibiting greatly increased plasma half-life and a significantly lower accumulation in non-target organs.
  • these improved radiopharmaceuticals provide superior tumor imaging capabilities by reducing the amount of background radiation from non-target tissues, and the rapid clearance of the compounds from non-target organs also allows for an increase in the radiation dosimetry of the radiopharmaceutical. for further enhancement of tumor imaging capabilities and cytotoxic cancer therapy.
  • the nature of the phospholipid ether compounds which exhibit these enhanced capabilities are compounds having an extension of the carbon chain bearing the radiolabelled phenyl group.
  • Previous studies with related alkyl phosphocholine analogs had demonstrated that blood levels actually decreased with increasing chain length, while tumor levels increased. See, e.g. , Kotting et ai. "Alkylphosphocholines: influence of structural variation on biodistribution at antineoplastically active concentrations.” Cancer Chemother. Pharm. 30: 105-1 12 ( 1992).
  • the improved compounds of the present invention have displayed a propensity to remain in the circulation much longer than the original shorter chain analogs, and the delayed clearance from the blood plasma advantageously results in additional opportunities for uptake of the radiopharmaceuticals by tumor tissue as they continuously circulate through the vasculature.
  • the improved phospholipid ether analogs of the present invention are cytotoxic to tumor cells, even without the presence of a radioactive isotope in the compound. Therefore, the inclusion of a long-lived radioactive isotope of iodine, for example, yields tumor-specific radiopharmaceuticals which are tissue-destructive by more than one mode.
  • the following examples relate to specific embodiments and methods of using the improved radiolabelled phospholipid analogs of the present invention, and include illustrative methods for synthesizing the analogs. All starting materials and reagents were obtained from Aldrich Chemical Company, Milwaukee. Wisconsin.
  • EXAMPLE 2 Further conversion of 18-(p-iodophenyl) octadecanol into the desired phosphocholines was performed as described in detail for the C-12 analogs in Rampy et al.. "Synthesis and biological evaluation of radio-iodinated phospholipid ether analogs," Nucl. Med. Biol. 22, 505- 512 (1995).
  • the improved phospholipid ether analog contemplated by the present invention is a simple straight chain alkyl phospholipid.
  • 18-(p- iodophenyl)octadecyl phosphocholine (Compound XVI). The synthesis of Compound XVI was accomplished according to the illustrative preparatory scheme shown in Figure 2.
  • the improved phospholipid ether analogs contemplated by the present invention are constructed using a propanediol backbone.
  • the synthesis of l-0-[18-(p-Iodophenyl)octadecyl]-l ,3-propanediol-3-phosphocholine (Compound XIV) was accomplished according to the illustrative preparatory scheme shown in
  • Compound X was debenzylated by AlCl 3 -anisole as described for the synthesis of Compound VI, to produce Compound XII, l-0-[18-(p-Iodophenyl)octadecyl]-l,3-propanediol (50 mg; 0.08 mmol). (42 mg, 99 % yield). Finally, the desired phosphocholine XIV was synthesized above from the alcohol XII (42 mg; 79 mmol) in an analogous manner to that described in Example 2 for Compound XVI. (45 mg, 55 % yield).
  • EXAMPLE 4 This example illustrates yet another preferred embodiment of the improved phospholipid ether analogs contemplated by the present invention, wherein the hydrogen located at the 2-position of Compound XIV is replaced with an O-mefhyl group.
  • the synthesis of l- ⁇ -[18-(p-Iodophenyl)octadecyl]-2-0-methyl-r ⁇ c-glycero-3-phosphocholine (Compound XV) was accomplished according to the illustrative preparatory scheme shown in Figure 4.
  • Radioiodination of Phospholipid Ether Analogs For certain uses, such as scintigraphy or experimental evaluation of tissue distribution, it is desirable to create radioactive compounds. Radioiodination of the iodinated phospholipid ether analogues disclosed herein, or one of the intermediates in the synthesis pathway, can be accomplished by a variety of techniques, some of which are known in the art. For example, aromatic compounds with electron donating groups (such as anilines) can be radiolabelled by electrophilic iodination in the presence of radioiodine. iodine monochloride. chloramine-T, iodogen. etc.
  • Unactivated aromatic rings can be radioiodinated by exchange of a leaving group, such as aryl boronic acids, aryl thallium trifluoroacetates. triazenes or metallated arenes with radioiodine.
  • a leaving group such as aryl boronic acids, aryl thallium trifluoroacetates. triazenes or metallated arenes with radioiodine.
  • Direct electrophilic radioiodination of a phenyl ring is yet another alternative, but may produce isomeric mixtures which are difficult to separate. Iodine exhange of aryl iodides with radioiodine may be a preferable approach insofar as no complex separation techniques are necessary, since the substrate and radioiodinated product are chemically identical.
  • an isotope exchange-type technique is utilized wherein the substrate and radioiodine are reacted at an elevated temperature in a "melt."
  • the molten reaction medium possesses a sufficiently high dielectric constant to solubilize both the substrate and radioiodide.
  • reaction media currently in use are benzoic acid (mp 122°C, bp 249°C.) and acetamide (mp 182°C, bp 221 °C).
  • an acidic exchange medium comprising pivalic acid, a homolog of acetic acid, also known as trimethyl acetic acid, can be used.
  • Pivalic acid has a melting point of 33°C. and a boiling point of 164°C.
  • Absolute ethanol (20 ⁇ l) was added via a microliter syringe, followed by aqueous Na l25 l (0.5-3.0 mCi, 2-10 ⁇ l) (no-carrier-added in reductant-free 0.1 N NaOH from Amersham Radiochemicals). The vial was gently swirled to dissolve the contents and ensure homogeneity.
  • HPLC column eluted with hexane/isopropanol/water (40:52:8) at 0.8 ml/min. Peaks were analyzed by both UV (230 and 254 nm) and radiodetection. After pooling appropriate fractions, the radiochemical purity of the final product was monitored by TLC (gamma and UV detection) and by HPLC (UV at 230254 nm and radiochemical detector). Fractions were combined and the solvent was removed with a gentle stream of nitrogen. HPLC analysis of the final compound confirmed both chemical (UV at 230/254 nm) and radiochemical (radioactivity) purity. Of course, any isotope of iodine such as the clinically used isotopes, 122 I. 123 I, l25 I and
  • 13 I I can be used. I25 I is preferred for in vitro work in the laboratory due to its relatively long half-life. For radiodiagnostic purposes in humans, 123 I or 13 I I are preferred due to their shorter half-lives and favorable imaging energies. Thus, the radioiodination procedure described above may be modified, as known by those of skill in the art, to compensate for the difference in half-life.
  • the radioiodinated phospholipid ether analogs of the present invention may be solubilized in a suitable transport agent or carrier vehicle, and administered to mammalian subjects as radiologic agents by any known manner, preferably parentally such as intravenously or intraperitonally. It is not intended that the present invention be limited by the particular nature of the therapeutic preparation.
  • such compositions can be provided together with physiologically tolerable liquid, gel or solid carriers, diluents, adjuvants and excipients.
  • therapeutic preparations can be administered to mammals for veterinary use, such as with domestic animals, and clinical use in humans in a manner similar to other therapeutic agents.
  • dosage required for therapeutic efficacy will vary according to the type of use and mode of administration, as well as the particularized requirements of individual hosts.
  • compositions are typically prepared as liquid solutions or suspensions, or in solid forms.
  • Oral formulations for cancer usually will include such normally employed additives such as binders, fillers, carriers, preservatives, stabilizing agents, emulsifiers. buffers and excipients as. for example, pharmaceutical grades of mannitol. lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like.
  • These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations, or powders, and typically contain l%-95% of active ingredient, preferably 2%-70%.
  • compositions are also prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection may also be prepared.
  • the radioiodinated compounds of the present invention are often mixed with diluents or excipients which are physiologically tolerable and compatible. Suitable diluents and excipients are, for example, water, saline, dextrose, glycerol. or the like, and combinations thereof.
  • the compositions may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, stabilizing or pH buffering agents.
  • Additional formulations which are suitable for other modes of administration, such as topical administration include salves, tinctures, creams, lotions, and. in some cases, suppositories.
  • traditional binders, carriers and excipients may include, for example, polyalkylene glycols or triglycerides.
  • Walker-256 carcinosarcoma cells (5 x 10 6 cells) in 0.2 ml saline in the right hindlimb.
  • the Walker carcinoma cell line was provided by Dr. James Varani of the Department of Pathology at the University of Michigan, and is an accepted cell line representative of effect in humans. See, e.g. Tayck et al., "Influence of the Walker 256 Carcinosarcoma on Muscle. Tumor, and Whole-Body Protein Synthesis and Growth Rate in the Cancer-Bearing Rat, Cancer Res.
  • the animals were used 6-8 days later when the tumor weight averaged 10 g.
  • the radiolabelled compounds were dissolved in absolute ethanol (50-500 ⁇ l) and Tween-20 (0.1 ml/mg of compound) was added to the solution. Ethanol was removed by evaporation under a stream of nitrogen. Physiological saline or sterile water was added, to give a 2-3% Tween-
  • the solubilized radiolabelled compounds (5-10 ⁇ Ci, 0.3 ml) were administered intravenously via the tail vein to tumor bearing rats, and the animals were sacrificed by exsanguination while under ether anesthesia at the various time points. Blood samples were collected through cardiac puncture and selected tissues (liver, kidney, etc.) were removed, trimmed, blotted to remove excess blood and weighed. Large organs were thoroughly minced with scissors to obtain random representative tissue samples. For the biodistribution experiments with 12-(/ iodophenyl)dodecyl phosphocholine, weighed tissue samples were counted with a well scintillation counter (85% counting efficiency). The concentration of radioactivity in each tissue was expressed as a percentage of administered dose per gram of tissue.
  • Tissue distribution was assessed at various times following administration of the radioiodinated chain length isomers.
  • An illustration of the data for each analog is set forth in Table 1 below. The results are expressed as the mean % administered dose per gram ⁇ SEM (% Dose/g ⁇ SEM).
  • the clearance of the C18 analog from non-target tissues was much more rapid than from tumor, and the quantities of radioactivity detected in the liver, kidney and duodenum were significantly lower following administration of the C18 analog, as compared to the same organs in the C15 and C12 analog studies.
  • the C18 analog was retained in the circulation to a much greater extent than the other chain length isomers surveyed.
  • Table 1 illustrates, the plasma level for the C- 18 analog was significantly higher than the plasma levels for both the C-12 and the C-15 analog.
  • Dunning prostate tumor cells 1 x 10 6 MAT-LyLu cells
  • the MAT-LyLu subline of the Dunning (R-3327) adenocarcinoma prostate tumor was provided by Dr. Ken Pienta of the Department of Urology at the University of Michigan, and is an accepted cell line representative of effect in humans. See, e.g., Pienta et al., "Inhibition of
  • the animals were maintained with free access to food and water until day 8-10.
  • the radioiodinated phospholipid ether analog formulated in 2% Tween 20 - sterile water (5-10 ⁇ Ci, 0.3-0.4 ml. described above in Example 6) was administered intravenously into the tail vein of the tumor-bearing animals under metofane anesthesia.
  • the C-18 analogs again demonstrated kidney and liver levels several times lower than the C-12 analog in the prostate tumor model.
  • the longer chain analogs also demonstrated a superior tumor avidity, with tumor levels of Compound XVI more than twice as high as the shorter chain analog.
  • the improved compounds of the present invention may find particularly advantageous use in the imaging and/or treatment of prostate tumors.
  • the anesthetized animals were imaged at selected times after injection on a gamma camera set to the 125 I window and outfitted with a low energy coilimator. Static fifteen-minute images were obtained for each animal at the specified time. The results are illustrated in Figures 8A-8C.
  • the compounds of the present invention may find applicability as carrier molecules for radiosensitizers.
  • Radiosensitizers are agents administered to sensitize tumor tissue to the effects of externally applied radiation.
  • Well known radiosensitizers such as misonidazole and metronidazole are substituted nitroimidazoles.
  • Substitution of an electron-capturing moiety, such as nitroimidazole. for the iodophenyl moiety in the phospholipid ether analogues of the present invention would permit tumor-localized sensitization for radiation therapy.
  • the phospholipid analogues of the present invention could incorporate boron containing substituents for use as boron-neutron activation therapeutic agents. These therapeutic agents are administered using the stable isotope of the electron- capturing boron. External radiation activates the boron to create tissue destructive activity.
  • the invention contemplates any one of the ortho-, meta- and para-isomers of iodobenzyl as the iodine-bearing moiety.

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Abstract

L'invention concerne des analogues radio-iodés d'éthers de phospolipidiques qui présentent une importante avidité pour les tumeurs et ont une demi-vie dans le plasma plus longue que les analogues à chaîne plus courte; ils améliorent l'imagerie et le visualisation des lésions néoplasiques et permettent une thérapie cytotoxique du cancer spécifique des tumeurs.
PCT/US1996/019352 1996-12-04 1996-12-04 Analogues radio-iodes d'ethers phospholipidiques et leurs procedes d'utilisation WO1998024480A1 (fr)

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Application Number Priority Date Filing Date Title
CA002276284A CA2276284C (fr) 1996-12-04 1996-12-04 Analogues radio-iodes d'ethers phospholipidiques et leurs procedes d'utilisation
PCT/US1996/019352 WO1998024480A1 (fr) 1996-12-04 1996-12-04 Analogues radio-iodes d'ethers phospholipidiques et leurs procedes d'utilisation
US09/319,406 US6255519B1 (en) 1996-12-04 1996-12-04 Radioiodinated phospholipid ether analogs and methods of using the same
US09/898,178 US6417384B1 (en) 1996-12-04 2001-07-03 Radioiodinated phospholipid ether analogs and methods of using the same

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Cited By (8)

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WO2007013894A2 (fr) * 2004-12-20 2007-02-01 Cellectar, Llc Analogues d'ether phosppholipidique utilises comme agents anti-cancereux et methodes correspondantes
JP2013504590A (ja) * 2009-09-11 2013-02-07 セレクター，インコーポレイティド 非放射性リン脂質化合物、組成物、及び使用方法
US8535641B2 (en) 2004-03-02 2013-09-17 Cellectar, Inc. Phospholipid analogs as diapeutic* agents and methods thereof
US8540968B2 (en) 2004-03-02 2013-09-24 Cellectar, Inc. Phospholipid ether analogs as agents for detecting and locating cancer, and methods thereof
US20130343991A1 (en) * 2009-06-12 2013-12-26 Cellectar, Inc. Ether and alkyl phospholipid compounds for treating cancer and imaging and detection of cancer
US8871181B2 (en) 2009-05-11 2014-10-28 Cellectar, Inc. Fluorescent phospholipid ether compounds, compositions, and methods of use
US9616140B2 (en) 2009-05-11 2017-04-11 Cellectar Biosciences, Inc. Fluorescent phospholipid ether compounds, compositions, and methods of use
JP2017535608A (ja) * 2014-11-17 2017-11-30 セレクター・バイオサイエンシズ・インコーポレイテッド 癌標的化薬物ビヒクルとしてのリン脂質エーテル類似体

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