CA2284581A1 - Radiolabelled somatostatin receptor ligands for diagnosis and therapy - Google Patents
Radiolabelled somatostatin receptor ligands for diagnosis and therapy Download PDFInfo
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- CA2284581A1 CA2284581A1 CA002284581A CA2284581A CA2284581A1 CA 2284581 A1 CA2284581 A1 CA 2284581A1 CA 002284581 A CA002284581 A CA 002284581A CA 2284581 A CA2284581 A CA 2284581A CA 2284581 A1 CA2284581 A1 CA 2284581A1
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- 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
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- 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/083—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being octreotide or a somatostatin-receptor-binding peptide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention relates to a carrier substance for radionuclides used in the diagnosis and/or radiotherapy of somatostatin receptor-positive tumors or target cells. Said conjugate consists of somatostatin 14 agonists, lanreotide and a macrocyclic chelating agent former which forms stable chelates with metallic radionuclides in physiological conditions.
Description
RADIOLABELED SOMATOSTATIN RECEPTOR LIGANDS
FOR DIAGNOSIS AND THERAPY
The invention relates to a carrier substance for metal compounds for the diagnosis and/or destruction of tumor tissue, which selectively binds the substance to the somatostatin-binding surface receptors ofthe affected cells, where a macxocyclic chelating agent is bound to a somastostatin 14 agonist.
The increased expression of peptide receptors onto the most varied tumor cells forms the molecular basis for the use of radiolabeled peptides as part of nuclear-medicine localization diagnosis. One of the first molecules of this type, radio-iodized N-formyl-nle-leu-phe-nle-tyr-lys ( 1 ), was developed for the localization of abscesses on the basis of its binding to chemotactic receptors on neutrophile blood cells.
Subsequently, peptides such as (D)phe-cys-tyr-(D~rp-lys-thr-cys-thr(ol) (tyr3 octreotide, 2), and 1'~In-DTPA-(D)phe-cys-phe-(D)trp-lys-thr-cys-thr(ol) ((DTPA~(D)phel octreotide, 3) were used for the localization of malignant diseases, such as neuroendocrine tumors, breast cane, and lymphomas.
Another rr>ethod for detecting tumors is the technique of scintigraphy with radio-iodized VIP (vasoactive intestinal peptide, 4), which was developed in Vienna. This is a naturally occurring peptide. This radioligand (i.e.'~I-VIP) not only binds with high affnity to neuroendocrine tumors, but also to a large ntunbe< of ade~wcarcirwmas which cannot be made visible with 111In-DTPA-(D)phe' octreotide. It is noteworthy, however, that a number of primary tumors, such as carcinoids and insulinomas, can be shown both with'~I-VIP and with 111In-DTPA-(D)phel octreotide. In this connection, an interesting phenom~on was ob~rved in Vienna, namely that VIP and octreotide/somatostatin are cross-competitive for binding to tumor cell membranes.
W098/41540 P~CT/AT98/00063 Up to the present time, it has been possible to characterise and clone five different human somatostatin receptors (hSSTRI-5) and two different VIP
receptors.
Using transfected peptide receptors, it was found that the SSTR3 subtype among the somatostatin receptors is the most common binding site for somatostatin in tumor tissue.
It was also shown that VIP binds to SSTR3 and that these is cross-competition in binding of somatostatin and VIP to primary tumor cells.
Binding of peptides to tumor receptors can be used not only for localization diagnosis of tumors and their metastases. For example, the 'ilIn-DTPA-(D)phe' octreotide, which is used for diagnostic purposes, was also already used, at a high dose, as a receptor ligand for targeted radiotherapy.
From EP 0 714 911 A2, it is evident that a conjugate of an octapeptide, with the trivial name oc~reotide, and a macrocyclic chelat~ (DOTA) can complex a radionuclide in such a way that it can be used i» win for treatment of twnors.
This patent is limited to therapeutic use of the said substance. Octreotide binds only to some of the somatostatin 14 subtype recepxors that have beg found in the meantime, with high affinity. Ite viv~n,11 iIn_DTPA-(D~he' octreotide is also absorbed in the kidneys, liver, and spleen, which results in an unnecessarily high radiation stress on these organs.
The invention is now based on the task of creating a carries molecule ofthe type stated initially, which has as brood s somatostatin 14 receptor subtype recognition profile (hSSTR2-5) as possible and puts little bass on healthy tissue, so that is has better biodistribu#ion. The effect world be a higher dose in tumor tissue and lows radiation stress on healthy tissue, particularly the spleen and kidneys.
The same is also supposed to hold true if heavy metal atoms or par$rrsagnet<c n~tals are used instead of radionuclides.
The invention acx~o~nplished this task in that an octapeptide with the general formula t~~~-~~-zr'-t~~a'~~-r-v~-T~'a~ (~?
is bound to the macrocyclic chelating agent via its C or N terminus (Example 1), as the somatostatin 14 agonist. While this octapeptide is known by the designation "lanreotide,"
it is not known in combina~n with a macrocyclic chelating ag~t. The peptide of the inv~tion can be labeled with salts of radionuclides in metal-free buffers at elevated temperature (Examples 2 - 4). The high level of labeling efficiea;cy forms die starting basis for the formulation of a kit. The peptide of the invention forms a stable cd~elate with 1'lIn, 99Yb, or "'''~Ga, under physiological conditions. For example, these chelates are stable in human serum or in the presence of a 10,000 times excess of diethylene triamine pentaacetic acid (DTPA). The peptide of the invention also forms stable chelates with Rare Earths (M'T'b, ls3Sm, etc.).
EP O 714911 A2 covers the use of DOTA oc~treotide in a form l~eled with 9°"Y or '"Tb, as well a$ with radionuclides that emit alpha or bra particles, or auger electrons. Specifically, radionuclides that pass through an isomer transition (such as ~"Tc), capture electrons (i.e. 6'Ga, "'Ink or give offpositrons ('~Ga) are not mentioned (Example 8). The peptide of the invention can, in any case, be labeled with 1'lIn or ~'~Ga, in stable manner, and is therefore suitable not only for therapy, but also for use as a radiodiagnostic (both for SPFCT and PET).
The o~apeptide s~ccording io the inve~ion possesses a broad somatostatin receptor recognition profile. Specifically, the radioactively labeled pepride, with K~
values in tyre low nananolar range, bonds to SSTR2, SSTR3, SSTR4, and also SSTRS
(Example 5). The radiolabeled ligand also demonstrates a high binding amity for PC3 and DU145 prostate carcinoma cells, PANC1 and HT29 adenocarcinoma cells, A431 epithelial cells, ZR75-1 and T4?D breast cancer cells, as well as for 518A2 melanoma cells. Furthermore, the peptide binds to a number of primary tumors, such as breast cancer, melanomas, adenocarcinornas, lymphomas, liver cell tumors, thyroid tumors, and various neuroendocxine tumors. The mo$t importatzt somatoststin receptor expressed in the tumor appears to be SSTR3, which is a target R for the peptide of the invention (Example ~. The experiments showed that the binding behavior of the octapeptide, on the one hand, and that of the octapeptide combined with the macrocyclic chelating agent, on the other hand, was slightly different, which is probably attributable to the difference in lipophilia of the octapeptide in the w~bour~d and the bound date.
Biodi~ribution of the ~Y-labeled peptide in Sprague Dawley rats ( 180-220 g, 4 MB, 160 pmol) resulted in rapid elimination of the substance from the blood and a high absorption as well as r~ntion in the tissues which phy~ologically cxpress SSTR
(such as the pancreas). In contrast, absorption in organs which fly express no or only a little SSTR was charactarized by a very low absorption of radioactivity. For example, calculations for bone resulted in an absorption of only about 0.01 %/g of the injected dose, even 48 hours a#ter injection (Example 7).
Instead of the radionuclides listed, heavy meal atoms or metal ions with the atomic number 20-32, 42-44, 45 and 57 to 83 can also be us~od for medical imaging diagnosis. For magnetic resonance imaging, paramagnetic metals or metal ions with the atomic niunber 21-29, 42, 44 or 57-71, particularly Gd3+, Mns+, or Dy~+ can be used.
Furthermore, edkali, earth alkali, or transition metals or metal ions, particularly Na+, g+, Ca2+, Fe2+P+, Zn2+, and I~ln2+, can be used for pharmaceutical purposes.
It is advantageous to use die compound 1,4,7,10-ta~traazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) as the chelating agent. The conjugate resulting from lar~eotide and DOTA is relatively more lipophilic and demonstrates a slows blood clearance and higher tumor accumulation than other somatostatin 14 analogs in humans.
Because of the hydrophilia of DOTA, the lipophilia of the ocrapeptide that is used is reduced, which makes it easier to image the tumors, on the one hand, but on the other hand achieves a lower absorption of this substance in non-target organs, such as the spleen and the kidneys. In humans, the 111In-labeled peptide of the invention was compared directly with lIn-DTPA-(D)phel-octreotide. After intrav~ous administration of the peptide of the invention (3 mCi, 6 nmol), higher tumor absorption, lows retention in the kidneys, and reduced absorption in the spleen was found as compared with 111In-DTPA-(D)phel-octreotide (Example 8).
It is advantageous if 111In or ~Ga is bound to the chelating ag~t as the radionuclide for diagnosis; this has the advantage that this radionuclide emits garruna radi~ion, which is suitable for diagnosis, with lower radiation stress on the body. To destroy twnot tissue, 9°Y ~ the radioauclide can be bo~u~d to the chelating Wit; the forma is known to emit beta radiation, which serves to destroy the tumor cells, Snd therefore the elect of the radionuclide is essentially restricted to the diseased cells, because of the specif c binding of the octapeptide (Example 8). While ~'Y is well suited for trestrn~t of larger ttunors, because of its radiation range (B' radiation, 2.3 MeV), smaller can be btreated, in theory, with other fitting radio~ucdides such as isMb (B' rad~ion, 0. S and 0.6 ll~tV), or ls3Sm (B' radiation, 0.7 and 0.8 I4~eV), which can also be bound to the peptide of the invention. For this reas~, it world be possible to treat tatrwr patients (whose tumors express SSTR2-S, but particularly SSTR3) with a mixture of the peptide of the invention ("cocktail" of radionuclides, such as the'~Y-labeled peptide and the'6lTb-labeled peptide of the invention for radiotherapy). Also, a "cocktail" of radioisotopes (such as "Y-labeled peptide and the ~Y-labeled peptide) or radionuclides (such as 1'lIn-labeled peptide and the ~°Y-labeled pept;de) can be produced fcN simultaneous di~osis and radiotherapy.
W098/41540 PCT/AT98l0006S
For monitoring during therapy, the radioactively labeled peptide can be repeatedly used to evaluate somatostatin receptor-positive tumor diseases or endocrinological diseases.
a Exampk 1: Chemical Synthesis of the Peptide Abbreviations:
DOTA: 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid LANREOTmE:
~~~-~~-TYr-~~T=P-~-YT~~
i.1 BOC: tart.-butyloxycarbonyl 80 mg DOTA, 74 mg N-hydroJCy succinimide, and 80 mg [s-boc-lys']
lanreotide are dissolved in 15 mL H20 and 30 mL N,N-dime~yl formar~tide. One hundred mg of N,N'-di-cyclolaexyl cxrbod;imide are added and the resulting solution is stirred ~ room temperature for 16 hours. The product, [a-DOTA-(D~-t;nah, s-boc-lyssl lanreotide, is isolated and purified as a solvent using a silica gel 60 column, and using methylerie chloride : methaiwl : 50'/~ acetic acid (9:1:0.125 -> 7:3 :1 ). The boc-protaded group is split off from the [a-DOTA-(D}-Bnal', s-boc-lys'] lanrootide product (30 minutes ~ room teanp~ature). The resulting product, [a-DOTA-(D~Linal]
l~reotide, is precipitated using and purified using a C 18 Reverse Phase HPLC cohur~n, using a water / acetonitrik I / 0.1% trifluoroacetic acid solvent mixture. A second HPLC
purification step is added, using a water / acetonitrile / 1 °/s acetic acid solvent mixture, in order to obtain the pure product of the invention as an acetate salt.
FAB-MNH+: 1482 v ors o ~r_~
N
~~~'p,~!
d Conjugation st the N terminus ,,a~1 ~Nt~t ° s~ ~ o o a H~ a HO
Conjugation ~ the C terminus Ezample 2: Radiolabeling the peptide with lliIn The peptide of the invention is dissolved in 0.2 moleJL ammonium acetate buffs (metal-free, pH 7) and incubated with 1"InCI~ (carrier-free, Ivle~ < 0.1 pg / mCi, < 1 pg / mL) in 0.05 moleJL HCI. A ratio of 0.5 mCi 111In : 1 nmd DOTA
lanreotide is adjusted, and the reaction mixture is boiled at 100 °C for 30 minutes.
An aliquot is checked for purity using thin-layer chromatography. Typically, the radiochemical purity of the product is >99%. If it is less, the product is purified using Reverse Phase LC or HPLC. The radioligand is dissolved in a solution of 0.075 mole/L NaCI, 0.05 mole/L
NH,OAc, 0.2 mole/L ascorbic acid, and 0.1°/. human serum albumin, and sterilized by filtration through an 0.2 pm membrane.
Ezample 3: Radiolabeling the peptide with ~Y
Like Example 2, but instead of 111In, 9°Y is used (1 mCi : 1 nrnol DOTA
lanreotide).
Ezampie 4: Radiolabeling the peptide with ~~Ga Instead of 111In, 6'~Ga is used to radiolabel the peptide of the invention.
Ezample 5: In vitro binding o#'the'mIn/~Y labeled peptide The labeled and the unlabeled substance of the invention were investigated in saturation studies as well as in competition studies, with regard to their binding to diverse tumor cells (primary tumors, immortal cells), as well as to the somatostatin receptor subtypes SSTRl -SSTRS. For this purpose, the subtype receptors were expressed on COS-7 cells, using cDNA samples. Comparison studies were conducted with other somatostatin receptor agonists. In comparison studies, mI-tyri-somatostatin 14 was also used as a radioligand. There was no significant difference b~ween the 111In-labeled peptide and the ~Y-labeled peptide of the invention, with regard to binding behavior. The following data, however, clearly show that these is a significant dii~er~ce b~veea~ the peptide of the invention and "'In_DTPA-{D)Phel octreotide, with regarding to binding to SSTIt3 and to SSTR4.
i ~8~~ p v N n n n n n ~ ~ N ~ n ~ ~n ., ., n d ~ ~>..
~' N et c~1 N O O ~ Y1 h E" ~ n O C ~ C ~-~ ~ N n n ~ v1 ~
O
H ;°~
~1 ~°c .. ~ n oo~o ~~e~. n n ~~N
...
.r a I
f~ --A
h l'~ M ~ !rl !'~1 h !~ Y1 Nf ~-~ ~ ~-~ C vC ~ t~1 tV ~ O
n 'C ~ ~, ~ rf CC v1 O N O N ~f o0 Cs H ~ O O Poi O ~~.~ .-i ..i .r .-i ~.i ..i .~ ..w O
~ O !"rf v1 !r1 ~-~ N o0 00 r~ O .-w O
_ ~ .r C~ eh ~ C ~r1 er1 O c~f O ,-r ..~ .-r H
'/
w ' C ~ ~ ~ ~' E.
(<.~'''? <'[.d.~''? E,d"~v~ [.d.~'~? [.d.~"'~?
~~a ~ ~
PG"f/AT98/00065 Example 6: Tumors expressing somatostatin receptor subtype Stomach cancer, colon cancer, and cancer of the small intestine; skin cancer; breast cancer; cancer ofthe pancreas, thyroid tumors, lymphomas, lung cancer, various neuroendocrine tumors such as carcinoida, gastrinomas, pheochromocytomas;
prostate cancer, glandular cancer, and metastases ot'these tumors.
Ezampk 7: Biodistribution of the "Y-labeled peptide in animal ezperimenta The biodistribution of the 9'Y-labeled peptide of the invention was studied in rats. For this purpose, the radiolabeled peptide was administered intravenously to the caudal vein of Sprague Dawley rats (180-220 g, 4MBq,160 pmol~
The rab were killed after 1, 24, and 48 hours, and the organ: were removed.
The following distribution of radioactivity was found.
Tissue 16our p.i. 24 hours 48 boors '/. Inj. Dose/g '~. Inj. Dose/g'~ Inj. Dose/g (n a 4) (n ~ 3) (n = 3) Blood 0.24 t 0.04 0.01 t 0.004 0.006 t A.001 Heart 0.10 t 0.05 A.006 t 0.001 0.004 t 0.001 Lungs 0.28 t 0.10 0.05 t A.Ol 0.03 t 0.006 Liver A.16 t A.02 0.21 t 0.03 0.13 t 0.005 Spleen 0.12 t 0.04 0.06 f A.Ol 0.05 t 0.008 Kidneys 2.41 t 0.64 2.10 t 0.50 1.81 t A.45 Pancreas 1.12 t 0.27 0.55 t 0.24 0.35 t A.13 Adrenal glands 4.30 t 0.61 2.14 t A.83 2.OZ t 0.92 Hypophysis 1.69 t A.88 1.34 t 0.50 1.02 t 0.3A
Muscle A.03 t 0.02 0.003 t 0.001 0.003 t 0.001 Spinal columa O.lA t 0.04 0.02 t A.005 0.02 t A.003 Sternum 0.16 t 0.06 0.01 t 0.001 0.01 t 0.006 This distribution shows that all the organs that are known to express somatostatin receptor: possess a significantly greater absorption. The relatively low absorption in the spleen and liver (non-target organs) is also noteworthy. The absorption of the substance in the skeletal system is very low, even 48 hours after administration; this indicates the high in vivo stability of the 9°Y-labeled peptide of the invention.
Example 8: Biodistribution and dosimetry of the lilln-labeled peptide in humans The biodistribution and dosimetry of the 111In-labeled peptide of the invention were compared with the biodistribution and dosimetry of ll'In-DTPA-(D~
phel-octreotide. For this purpose, approximately 3 m~ or the one or the other substances were administered intravenously, at intervals of approximately six to eight weeks. Subsequent to the administration, blood samples, urine samples, as well as fecal samples were studied at various points in time, with regard to their radioactivity. The gamma radiation was recorded using a gamma camera, with the measurement points being set up to 144 hours after administration. The gamma camera recordings included whole-body images in anterior and posterior projection, as weU as a single-photon emissioa tomography (SPET) for a more precise tumor localization and size estimate. The relative ab:orptioa in individual organs and tumon and/or metastases was determined by establishing regions of interest."
Dosimetry data were extrapolated using the MIRD program.
The results ef t4e comparison between l~lIn-DTPA-octreotide and "'In-DOTA lanreotide are graphically shown in the drawing, in FIG. lA to FIG.1D.
From FIG. lA, ~ is ~ident that the substance of the iaventioo is excreted from the body somewhat more sbwly in comparison with'1'Ia-DTPA-(D~-pbel-octreotide. Absorption of the peptide of the invention in tumors is significantly greater, is a direct compariwn (see FIG.1B~ It is also important tbat in comparison with'i'In-DTPA-(D~phe'-octreotide, the peptide of the invention demonstrates a significantly lower absorption in the spleen (FIG.1C7 and the kidneys (FIG.1D~, a priori. This biodiatribution forms the basis for an effective radiotherapy with the 9'Y labeled peptide of the invention, since these organs are critical for radiation stress
FOR DIAGNOSIS AND THERAPY
The invention relates to a carrier substance for metal compounds for the diagnosis and/or destruction of tumor tissue, which selectively binds the substance to the somatostatin-binding surface receptors ofthe affected cells, where a macxocyclic chelating agent is bound to a somastostatin 14 agonist.
The increased expression of peptide receptors onto the most varied tumor cells forms the molecular basis for the use of radiolabeled peptides as part of nuclear-medicine localization diagnosis. One of the first molecules of this type, radio-iodized N-formyl-nle-leu-phe-nle-tyr-lys ( 1 ), was developed for the localization of abscesses on the basis of its binding to chemotactic receptors on neutrophile blood cells.
Subsequently, peptides such as (D)phe-cys-tyr-(D~rp-lys-thr-cys-thr(ol) (tyr3 octreotide, 2), and 1'~In-DTPA-(D)phe-cys-phe-(D)trp-lys-thr-cys-thr(ol) ((DTPA~(D)phel octreotide, 3) were used for the localization of malignant diseases, such as neuroendocrine tumors, breast cane, and lymphomas.
Another rr>ethod for detecting tumors is the technique of scintigraphy with radio-iodized VIP (vasoactive intestinal peptide, 4), which was developed in Vienna. This is a naturally occurring peptide. This radioligand (i.e.'~I-VIP) not only binds with high affnity to neuroendocrine tumors, but also to a large ntunbe< of ade~wcarcirwmas which cannot be made visible with 111In-DTPA-(D)phe' octreotide. It is noteworthy, however, that a number of primary tumors, such as carcinoids and insulinomas, can be shown both with'~I-VIP and with 111In-DTPA-(D)phel octreotide. In this connection, an interesting phenom~on was ob~rved in Vienna, namely that VIP and octreotide/somatostatin are cross-competitive for binding to tumor cell membranes.
W098/41540 P~CT/AT98/00063 Up to the present time, it has been possible to characterise and clone five different human somatostatin receptors (hSSTRI-5) and two different VIP
receptors.
Using transfected peptide receptors, it was found that the SSTR3 subtype among the somatostatin receptors is the most common binding site for somatostatin in tumor tissue.
It was also shown that VIP binds to SSTR3 and that these is cross-competition in binding of somatostatin and VIP to primary tumor cells.
Binding of peptides to tumor receptors can be used not only for localization diagnosis of tumors and their metastases. For example, the 'ilIn-DTPA-(D)phe' octreotide, which is used for diagnostic purposes, was also already used, at a high dose, as a receptor ligand for targeted radiotherapy.
From EP 0 714 911 A2, it is evident that a conjugate of an octapeptide, with the trivial name oc~reotide, and a macrocyclic chelat~ (DOTA) can complex a radionuclide in such a way that it can be used i» win for treatment of twnors.
This patent is limited to therapeutic use of the said substance. Octreotide binds only to some of the somatostatin 14 subtype recepxors that have beg found in the meantime, with high affinity. Ite viv~n,11 iIn_DTPA-(D~he' octreotide is also absorbed in the kidneys, liver, and spleen, which results in an unnecessarily high radiation stress on these organs.
The invention is now based on the task of creating a carries molecule ofthe type stated initially, which has as brood s somatostatin 14 receptor subtype recognition profile (hSSTR2-5) as possible and puts little bass on healthy tissue, so that is has better biodistribu#ion. The effect world be a higher dose in tumor tissue and lows radiation stress on healthy tissue, particularly the spleen and kidneys.
The same is also supposed to hold true if heavy metal atoms or par$rrsagnet<c n~tals are used instead of radionuclides.
The invention acx~o~nplished this task in that an octapeptide with the general formula t~~~-~~-zr'-t~~a'~~-r-v~-T~'a~ (~?
is bound to the macrocyclic chelating agent via its C or N terminus (Example 1), as the somatostatin 14 agonist. While this octapeptide is known by the designation "lanreotide,"
it is not known in combina~n with a macrocyclic chelating ag~t. The peptide of the inv~tion can be labeled with salts of radionuclides in metal-free buffers at elevated temperature (Examples 2 - 4). The high level of labeling efficiea;cy forms die starting basis for the formulation of a kit. The peptide of the invention forms a stable cd~elate with 1'lIn, 99Yb, or "'''~Ga, under physiological conditions. For example, these chelates are stable in human serum or in the presence of a 10,000 times excess of diethylene triamine pentaacetic acid (DTPA). The peptide of the invention also forms stable chelates with Rare Earths (M'T'b, ls3Sm, etc.).
EP O 714911 A2 covers the use of DOTA oc~treotide in a form l~eled with 9°"Y or '"Tb, as well a$ with radionuclides that emit alpha or bra particles, or auger electrons. Specifically, radionuclides that pass through an isomer transition (such as ~"Tc), capture electrons (i.e. 6'Ga, "'Ink or give offpositrons ('~Ga) are not mentioned (Example 8). The peptide of the invention can, in any case, be labeled with 1'lIn or ~'~Ga, in stable manner, and is therefore suitable not only for therapy, but also for use as a radiodiagnostic (both for SPFCT and PET).
The o~apeptide s~ccording io the inve~ion possesses a broad somatostatin receptor recognition profile. Specifically, the radioactively labeled pepride, with K~
values in tyre low nananolar range, bonds to SSTR2, SSTR3, SSTR4, and also SSTRS
(Example 5). The radiolabeled ligand also demonstrates a high binding amity for PC3 and DU145 prostate carcinoma cells, PANC1 and HT29 adenocarcinoma cells, A431 epithelial cells, ZR75-1 and T4?D breast cancer cells, as well as for 518A2 melanoma cells. Furthermore, the peptide binds to a number of primary tumors, such as breast cancer, melanomas, adenocarcinornas, lymphomas, liver cell tumors, thyroid tumors, and various neuroendocxine tumors. The mo$t importatzt somatoststin receptor expressed in the tumor appears to be SSTR3, which is a target R for the peptide of the invention (Example ~. The experiments showed that the binding behavior of the octapeptide, on the one hand, and that of the octapeptide combined with the macrocyclic chelating agent, on the other hand, was slightly different, which is probably attributable to the difference in lipophilia of the octapeptide in the w~bour~d and the bound date.
Biodi~ribution of the ~Y-labeled peptide in Sprague Dawley rats ( 180-220 g, 4 MB, 160 pmol) resulted in rapid elimination of the substance from the blood and a high absorption as well as r~ntion in the tissues which phy~ologically cxpress SSTR
(such as the pancreas). In contrast, absorption in organs which fly express no or only a little SSTR was charactarized by a very low absorption of radioactivity. For example, calculations for bone resulted in an absorption of only about 0.01 %/g of the injected dose, even 48 hours a#ter injection (Example 7).
Instead of the radionuclides listed, heavy meal atoms or metal ions with the atomic number 20-32, 42-44, 45 and 57 to 83 can also be us~od for medical imaging diagnosis. For magnetic resonance imaging, paramagnetic metals or metal ions with the atomic niunber 21-29, 42, 44 or 57-71, particularly Gd3+, Mns+, or Dy~+ can be used.
Furthermore, edkali, earth alkali, or transition metals or metal ions, particularly Na+, g+, Ca2+, Fe2+P+, Zn2+, and I~ln2+, can be used for pharmaceutical purposes.
It is advantageous to use die compound 1,4,7,10-ta~traazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) as the chelating agent. The conjugate resulting from lar~eotide and DOTA is relatively more lipophilic and demonstrates a slows blood clearance and higher tumor accumulation than other somatostatin 14 analogs in humans.
Because of the hydrophilia of DOTA, the lipophilia of the ocrapeptide that is used is reduced, which makes it easier to image the tumors, on the one hand, but on the other hand achieves a lower absorption of this substance in non-target organs, such as the spleen and the kidneys. In humans, the 111In-labeled peptide of the invention was compared directly with lIn-DTPA-(D)phel-octreotide. After intrav~ous administration of the peptide of the invention (3 mCi, 6 nmol), higher tumor absorption, lows retention in the kidneys, and reduced absorption in the spleen was found as compared with 111In-DTPA-(D)phel-octreotide (Example 8).
It is advantageous if 111In or ~Ga is bound to the chelating ag~t as the radionuclide for diagnosis; this has the advantage that this radionuclide emits garruna radi~ion, which is suitable for diagnosis, with lower radiation stress on the body. To destroy twnot tissue, 9°Y ~ the radioauclide can be bo~u~d to the chelating Wit; the forma is known to emit beta radiation, which serves to destroy the tumor cells, Snd therefore the elect of the radionuclide is essentially restricted to the diseased cells, because of the specif c binding of the octapeptide (Example 8). While ~'Y is well suited for trestrn~t of larger ttunors, because of its radiation range (B' radiation, 2.3 MeV), smaller can be btreated, in theory, with other fitting radio~ucdides such as isMb (B' rad~ion, 0. S and 0.6 ll~tV), or ls3Sm (B' radiation, 0.7 and 0.8 I4~eV), which can also be bound to the peptide of the invention. For this reas~, it world be possible to treat tatrwr patients (whose tumors express SSTR2-S, but particularly SSTR3) with a mixture of the peptide of the invention ("cocktail" of radionuclides, such as the'~Y-labeled peptide and the'6lTb-labeled peptide of the invention for radiotherapy). Also, a "cocktail" of radioisotopes (such as "Y-labeled peptide and the ~Y-labeled peptide) or radionuclides (such as 1'lIn-labeled peptide and the ~°Y-labeled pept;de) can be produced fcN simultaneous di~osis and radiotherapy.
W098/41540 PCT/AT98l0006S
For monitoring during therapy, the radioactively labeled peptide can be repeatedly used to evaluate somatostatin receptor-positive tumor diseases or endocrinological diseases.
a Exampk 1: Chemical Synthesis of the Peptide Abbreviations:
DOTA: 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid LANREOTmE:
~~~-~~-TYr-~~T=P-~-YT~~
i.1 BOC: tart.-butyloxycarbonyl 80 mg DOTA, 74 mg N-hydroJCy succinimide, and 80 mg [s-boc-lys']
lanreotide are dissolved in 15 mL H20 and 30 mL N,N-dime~yl formar~tide. One hundred mg of N,N'-di-cyclolaexyl cxrbod;imide are added and the resulting solution is stirred ~ room temperature for 16 hours. The product, [a-DOTA-(D~-t;nah, s-boc-lyssl lanreotide, is isolated and purified as a solvent using a silica gel 60 column, and using methylerie chloride : methaiwl : 50'/~ acetic acid (9:1:0.125 -> 7:3 :1 ). The boc-protaded group is split off from the [a-DOTA-(D}-Bnal', s-boc-lys'] lanrootide product (30 minutes ~ room teanp~ature). The resulting product, [a-DOTA-(D~Linal]
l~reotide, is precipitated using and purified using a C 18 Reverse Phase HPLC cohur~n, using a water / acetonitrik I / 0.1% trifluoroacetic acid solvent mixture. A second HPLC
purification step is added, using a water / acetonitrile / 1 °/s acetic acid solvent mixture, in order to obtain the pure product of the invention as an acetate salt.
FAB-MNH+: 1482 v ors o ~r_~
N
~~~'p,~!
d Conjugation st the N terminus ,,a~1 ~Nt~t ° s~ ~ o o a H~ a HO
Conjugation ~ the C terminus Ezample 2: Radiolabeling the peptide with lliIn The peptide of the invention is dissolved in 0.2 moleJL ammonium acetate buffs (metal-free, pH 7) and incubated with 1"InCI~ (carrier-free, Ivle~ < 0.1 pg / mCi, < 1 pg / mL) in 0.05 moleJL HCI. A ratio of 0.5 mCi 111In : 1 nmd DOTA
lanreotide is adjusted, and the reaction mixture is boiled at 100 °C for 30 minutes.
An aliquot is checked for purity using thin-layer chromatography. Typically, the radiochemical purity of the product is >99%. If it is less, the product is purified using Reverse Phase LC or HPLC. The radioligand is dissolved in a solution of 0.075 mole/L NaCI, 0.05 mole/L
NH,OAc, 0.2 mole/L ascorbic acid, and 0.1°/. human serum albumin, and sterilized by filtration through an 0.2 pm membrane.
Ezample 3: Radiolabeling the peptide with ~Y
Like Example 2, but instead of 111In, 9°Y is used (1 mCi : 1 nrnol DOTA
lanreotide).
Ezampie 4: Radiolabeling the peptide with ~~Ga Instead of 111In, 6'~Ga is used to radiolabel the peptide of the invention.
Ezample 5: In vitro binding o#'the'mIn/~Y labeled peptide The labeled and the unlabeled substance of the invention were investigated in saturation studies as well as in competition studies, with regard to their binding to diverse tumor cells (primary tumors, immortal cells), as well as to the somatostatin receptor subtypes SSTRl -SSTRS. For this purpose, the subtype receptors were expressed on COS-7 cells, using cDNA samples. Comparison studies were conducted with other somatostatin receptor agonists. In comparison studies, mI-tyri-somatostatin 14 was also used as a radioligand. There was no significant difference b~ween the 111In-labeled peptide and the ~Y-labeled peptide of the invention, with regard to binding behavior. The following data, however, clearly show that these is a significant dii~er~ce b~veea~ the peptide of the invention and "'In_DTPA-{D)Phel octreotide, with regarding to binding to SSTIt3 and to SSTR4.
i ~8~~ p v N n n n n n ~ ~ N ~ n ~ ~n ., ., n d ~ ~>..
~' N et c~1 N O O ~ Y1 h E" ~ n O C ~ C ~-~ ~ N n n ~ v1 ~
O
H ;°~
~1 ~°c .. ~ n oo~o ~~e~. n n ~~N
...
.r a I
f~ --A
h l'~ M ~ !rl !'~1 h !~ Y1 Nf ~-~ ~ ~-~ C vC ~ t~1 tV ~ O
n 'C ~ ~, ~ rf CC v1 O N O N ~f o0 Cs H ~ O O Poi O ~~.~ .-i ..i .r .-i ~.i ..i .~ ..w O
~ O !"rf v1 !r1 ~-~ N o0 00 r~ O .-w O
_ ~ .r C~ eh ~ C ~r1 er1 O c~f O ,-r ..~ .-r H
'/
w ' C ~ ~ ~ ~' E.
(<.~'''? <'[.d.~''? E,d"~v~ [.d.~'~? [.d.~"'~?
~~a ~ ~
PG"f/AT98/00065 Example 6: Tumors expressing somatostatin receptor subtype Stomach cancer, colon cancer, and cancer of the small intestine; skin cancer; breast cancer; cancer ofthe pancreas, thyroid tumors, lymphomas, lung cancer, various neuroendocrine tumors such as carcinoida, gastrinomas, pheochromocytomas;
prostate cancer, glandular cancer, and metastases ot'these tumors.
Ezampk 7: Biodistribution of the "Y-labeled peptide in animal ezperimenta The biodistribution of the 9'Y-labeled peptide of the invention was studied in rats. For this purpose, the radiolabeled peptide was administered intravenously to the caudal vein of Sprague Dawley rats (180-220 g, 4MBq,160 pmol~
The rab were killed after 1, 24, and 48 hours, and the organ: were removed.
The following distribution of radioactivity was found.
Tissue 16our p.i. 24 hours 48 boors '/. Inj. Dose/g '~. Inj. Dose/g'~ Inj. Dose/g (n a 4) (n ~ 3) (n = 3) Blood 0.24 t 0.04 0.01 t 0.004 0.006 t A.001 Heart 0.10 t 0.05 A.006 t 0.001 0.004 t 0.001 Lungs 0.28 t 0.10 0.05 t A.Ol 0.03 t 0.006 Liver A.16 t A.02 0.21 t 0.03 0.13 t 0.005 Spleen 0.12 t 0.04 0.06 f A.Ol 0.05 t 0.008 Kidneys 2.41 t 0.64 2.10 t 0.50 1.81 t A.45 Pancreas 1.12 t 0.27 0.55 t 0.24 0.35 t A.13 Adrenal glands 4.30 t 0.61 2.14 t A.83 2.OZ t 0.92 Hypophysis 1.69 t A.88 1.34 t 0.50 1.02 t 0.3A
Muscle A.03 t 0.02 0.003 t 0.001 0.003 t 0.001 Spinal columa O.lA t 0.04 0.02 t A.005 0.02 t A.003 Sternum 0.16 t 0.06 0.01 t 0.001 0.01 t 0.006 This distribution shows that all the organs that are known to express somatostatin receptor: possess a significantly greater absorption. The relatively low absorption in the spleen and liver (non-target organs) is also noteworthy. The absorption of the substance in the skeletal system is very low, even 48 hours after administration; this indicates the high in vivo stability of the 9°Y-labeled peptide of the invention.
Example 8: Biodistribution and dosimetry of the lilln-labeled peptide in humans The biodistribution and dosimetry of the 111In-labeled peptide of the invention were compared with the biodistribution and dosimetry of ll'In-DTPA-(D~
phel-octreotide. For this purpose, approximately 3 m~ or the one or the other substances were administered intravenously, at intervals of approximately six to eight weeks. Subsequent to the administration, blood samples, urine samples, as well as fecal samples were studied at various points in time, with regard to their radioactivity. The gamma radiation was recorded using a gamma camera, with the measurement points being set up to 144 hours after administration. The gamma camera recordings included whole-body images in anterior and posterior projection, as weU as a single-photon emissioa tomography (SPET) for a more precise tumor localization and size estimate. The relative ab:orptioa in individual organs and tumon and/or metastases was determined by establishing regions of interest."
Dosimetry data were extrapolated using the MIRD program.
The results ef t4e comparison between l~lIn-DTPA-octreotide and "'In-DOTA lanreotide are graphically shown in the drawing, in FIG. lA to FIG.1D.
From FIG. lA, ~ is ~ident that the substance of the iaventioo is excreted from the body somewhat more sbwly in comparison with'1'Ia-DTPA-(D~-pbel-octreotide. Absorption of the peptide of the invention in tumors is significantly greater, is a direct compariwn (see FIG.1B~ It is also important tbat in comparison with'i'In-DTPA-(D~phe'-octreotide, the peptide of the invention demonstrates a significantly lower absorption in the spleen (FIG.1C7 and the kidneys (FIG.1D~, a priori. This biodiatribution forms the basis for an effective radiotherapy with the 9'Y labeled peptide of the invention, since these organs are critical for radiation stress
Claims (14)
1. Carrier substance for a metal compound for the diagnosis and/or destruction of tumor tissue or other target cells, which substance selectively binds to the somatostatin-binding surface receptors of the affected cells, where a macrocyclic chelating agent is bound to a somastostatin 14 agonist, characterized in that an octapeptide with the general formula (I) is bound to the macrocyclic chelating agent via its C or N terminus, as the somatostatin 14 agonist.
2. Carries substance according to claim 1, characterized in that the compound 1,4,7,10-tetraazacyclododecane tetraacetic acid or the compound 1,4,8,11-tetraazacyclotetradecane-1',4',8',11'-tetraacetic acid (TETA) is used as the chelating agent.
3. Carrier substance according to claim 1 or 2, with a macrocyclic chelating agent bound to it, characterized in that the metal compound is a radionuclide.
4. Carrier substance according to claim 3, with a macrocyclic chelating agent bound to it, characterized in that 111In or 67Ga is bound to the chelating agent as a radionuclide for diagnosis.
5. Carrier substance according to claim 3, with a macrocyclic chelating agent bound to it, characterized in that 90Y as a radionuclide or also rare earths such as 153Sm, 166Ho, or 165Dy are bound to the chelating agent, for the purpose of destroying tumor tissue.
6. Carrier substance according to claim 3, with a macrocyclic chelating agent bound to it, characterized in that a corresponding nuclide such as 68Ga or 86Y is bound to the chelating agent, for the purpose of diagnosis by means of positron emission tomography.
7. Carrier substance according to claim 1 or 2, with a macrocyclic chelating agent bound to it, characterized in that the metal compound is a heavy metal atom or a metal ion with the atomic number 20-32, 42-44, 45 and 57 to 83, for medical imaging for diagnostic purposes.
8. Carrier substance according to claim 1, 2, or 7, with a macrocyclic chelating agent bound to it, characterized in that the metal compound is a paramagnetic metal or a metal ion with the atomic number 21-29, 42, 44, or 57-71, particularly Gd3+, Mn2+, or Dy3+, for nuclear magnetic resonance imaging.
9. Carrier substance according to claim 1 or 2, with a macrocyclic chelating agent bound to it, characterized in that the metal compound is a pharmaceutically safe alkali, earth alkali, or transition metal or a metal ion, particularly Na+, K+, Ca2+, Fe2+.beta.+, Zn2+, and Mn2+, for therapeutic purposes.
10. Use of the carrier substance coupled with a metal compound, according to one of claims 1 to 9, in a process for the production of an agent for diagnosis as well as therapy of target cells, such as tumor cells, or leukocyte accumulations, which express somatostatin receptor subtypes SSTR2, SSTR3, SSTR4, or SSTR5.
11. Use of the carrier substance coupled with a radionuclide, according to one of claims 3 and 5, in the production of an agent for treatment of target cells, in the form of a mixture of radionuclides, such as the 90Y-labeled peptide and the 161Tb-labeled peptide.
12. Use of the carrier substance coupled with a radionuclide, according to one of claims 3 and 6, in the production of an agent for diagnosis and therapy, in the form of a mixture of radioisotopes, such as 86Y-labeled peptide and 90Y-labeled peptide, or radionuclides, such as In-labeled peptide and 90Y-labeled peptide, for simultaneous diagnosis and radiotherapy.
13. Use of the carrier substance coupled with a radionuclide, according to one of claims 1 to 9, for the evaluation of somatostatin receptor-positive tumor diseases or endocrinological diseases, by means of repeated use of the marked peptide to check the result of therapy.
14. Process for the production of a compound according to claim 1, characterized in that a peptide compound according to Formula (i) or a derivative of it is brought to reaction with a macrocyclic chelating agent or a derivative of it, in order to obtain a chelate-peptide compound, and possibly to form a metal chelate complex from it.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0045197A AT405906B (en) | 1997-03-14 | 1997-03-14 | RADIO-MARKED SOMATOSTATIN RECEPTOR LIGANDS FOR DIAGNOSIS AND THERAPY |
| ATA451/97 | 1997-03-14 | ||
| PCT/AT1998/000065 WO1998041540A1 (en) | 1997-03-14 | 1998-03-12 | Radiolabelled somatostatin receptor ligands for diagnosis and therapy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2284581A1 true CA2284581A1 (en) | 1998-09-24 |
Family
ID=3490974
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002284581A Abandoned CA2284581A1 (en) | 1997-03-14 | 1998-03-12 | Radiolabelled somatostatin receptor ligands for diagnosis and therapy |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0975670A1 (en) |
| JP (1) | JP2001515494A (en) |
| AT (1) | AT405906B (en) |
| AU (1) | AU6602198A (en) |
| CA (1) | CA2284581A1 (en) |
| WO (1) | WO1998041540A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU6909700A (en) * | 1999-08-16 | 2001-03-13 | Uab Research Foundation | Gene transfer imaging and uses thereof |
| US6358491B1 (en) | 1999-08-27 | 2002-03-19 | Berlex Laboratories, Inc. | Somatostatin analogs |
| DE10002939C1 (en) * | 2000-01-13 | 2001-09-20 | Schering Ag | New aromatic-substituted tetraazacyclododecane-triacetic acid paramagnetic metal complex compounds, are useful as contrast agents for magnetic resonance imaging of necrotic or infarction tissue |
| ITMI20011708A1 (en) * | 2001-08-03 | 2003-02-03 | Bracco Imaging Spa | CONJUGATES OF PEPTIDES, THEIR DERIVATIVES WITH METALLIC COMPLEXES AND USE FOR DIAGNOSTIC INVESTIGATION THROUGH IMAGING FOR MAGNETIC RESONANCE (M |
| US7122622B2 (en) | 2002-04-16 | 2006-10-17 | Biosynthema Inc. | Peptide compounds having improved binding affinity to somatostatin receptors |
| EP1358890A1 (en) * | 2002-05-03 | 2003-11-05 | BioSynthema, Inc | Benzothienyl analogue of somatostatine, selective for certain somatostatin receptors |
| AU2015284236B2 (en) | 2014-06-30 | 2018-03-08 | Tva (Abc), Llc | Targeted conjugates and particles and formulations thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5590656A (en) * | 1992-09-15 | 1997-01-07 | The Ohio State University Research Foundation | Application of peptide/cell receptor kinetics utilizing radiolabeled somatostatin congeners in the in situ, in vivo detection and differentiation of neoplastic tissue |
| GB9417873D0 (en) * | 1994-09-06 | 1994-10-26 | Sandoz Ltd | Organic compounds |
| US5597894A (en) * | 1995-06-05 | 1997-01-28 | The Louisiana State University Medical Center Foundation | Multi-tyrosinated somatostatin analogs |
-
1997
- 1997-03-14 AT AT0045197A patent/AT405906B/en not_active IP Right Cessation
-
1998
- 1998-03-12 EP EP98907750A patent/EP0975670A1/en not_active Withdrawn
- 1998-03-12 JP JP53994098A patent/JP2001515494A/en active Pending
- 1998-03-12 WO PCT/AT1998/000065 patent/WO1998041540A1/en not_active Application Discontinuation
- 1998-03-12 CA CA002284581A patent/CA2284581A1/en not_active Abandoned
- 1998-03-12 AU AU66021/98A patent/AU6602198A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998041540A1 (en) | 1998-09-24 |
| AT405906B (en) | 1999-12-27 |
| EP0975670A1 (en) | 2000-02-02 |
| AU6602198A (en) | 1998-10-12 |
| JP2001515494A (en) | 2001-09-18 |
| ATA45197A (en) | 1999-05-15 |
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