Peptides

Details Peptides Peptides

2000-07-05

2001-08-21

Jones, Dameron L. (Department: 1619)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001110, C424S001650, C424S009100, C530S328000, C530S317000

Reexamination Certificate

active

06277356

ABSTRACT:

The present invention relates to somatostatin peptides, process for their production, pharmaceutical preparations containing them and their use as a radiopharmaceutical, e.g. for radiotherapy of somatostatin receptor positive tumors.
Radiotherapy of tumors with radioactive compounds has the advantages of selectively targeting tumors and their metastases, thus limiting the radiation dose to normal tissue. A radiotherapeutic agent should have a fast accumulation and high retention at the target organs, e.g. tumor, and a fast clearance from the circulation to limit the whole body radiation dose. A radiotherapeutic agent based on a chelated radiometal should also abe thermodynamically and/or kinetically stable against loss of the radiometal. A radiotherapeutic agent being administered repeatedly should not be immunogenic.
GB-A-2,225,579 discloses somatostatin peptides bearing at least one chelating group which can be radiolabelled for in vivo diagnostic and therapeutic applications. These compounds are capable of binding to somatostatin receptors, e.g. expressed or overexpressed by tumors or metastases. EP-A2-607,103 describes somatostatin peptides comprising a bifunctional polyaminopolycarboxylic acid chelating group attached to their terminal amino group by means of a spacer group. However, even though the presence of a bifunctional chelating group (octadentate) and of a spacer group lead to the improvement of certain properties of the resulting conjugate, there is still a compelling need for a radiopharmaceutical with further improved properties, particularly a high target/kidney ratio to minimize the radiation dose in the kidneys.
It has now been found that somatostatin peptides as disclosed hereinafter comprising a monofunctional DOTA (1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetraacetic acid) conjugated directly, i.e. in the absence of a spacer group, to the terminal amino group of the somatostatin peptides have improved properties. Particularly they have an improved tumor/kidney ratio hence a lower radiation dose delivered to the kidneys.
According to the invention there is provided a compound of formula I
wherein
M is H
+
or a cation and
A is Phe or Tyr,
in free form, salt form or complexed with a radionuclide.
As will be appreciated, any two nitrogen atoms in the “DOTA” portion of the above formula are connected by an ethylene group.
When A is Phe, the peptide moiety of the compound of formula I corresponds to octreotide. When A is Tyr, the peptide moiety corresponds to [Tyr
3
]-octreotide.
A is preferably Tyr.
M may be H
+
or any salt forming cation for a carboxy group, e.g. a monovalent or one equivalent of a polyvalent cation, for example an alkali metal ion such as sodium, potassium, or a substituted or unsubstituted ammonium ion.
Compounds of formula I may also exist e.g. in the form of an internal salt when M is H
+
or in the form of acid addition salts. Acid addition salts include e.g. salts obtained by addition of an organic, polymeric or inorganic acid, for example chlorhydrate, acetate, trifluoroacetate or lactate.
By radionuclide is meant an &agr;- or &bgr;-emitting nuclide or a nuclide with Auger-e
−
-cascades. Suitable nuclides include e.g.
64
Cu,
67
Cu or a radiolanthanide, particularly
90
Y,
140
La,
161
Tb,
169
Er
153
Sm,
177
Lu,
166
Dy,
166
Ho or
175
Yb, more preferably
161
Tb and
90
Y, most preferably
90
Y
The present invention also includes a process for the production of the compounds of formula I. They may be produced by analogy to known methods. The compounds of formula I may be produced for example as follows:
a) removing at least one protecting group which is present in a compound of formula I in protected form, or
b) linking together by an amide bond two peptide units, one of them containing at least one amino alcohol in protected or unprotected form and the other of them containing the DOTA group, wherein the amide bond is in such a way that the desired amino acid sequence of formula I is obtained, and stage a) of the process is then optionally effected, or
c) linking together DOTA and the desired somatostatin peptide in protected or unprotected form in such a way that the group derived from DOTA is fixed on the terminal amino group of the peptide, and stage a) is then optionally effected or,
d) oxidizing a DOTA-peptide having the amino acid sequence as stated in formula I wherein the mercapto groups of the Cys radicals exist in free form so as to produce a compound of formula I in which the 2 Cys radicals are joined by an S—S-bridge,
and recovering the compounds of formula I thus obtained in free form, in salt form or in complexed form with a radionuclide.
The above reactions may be effected in analogy with known methods, e.g. as described in the following examples. Where desired, in these reactions, protecting groups which are suitable for use in peptides or for the DOTA chelating group may be used for functional groups which do not participate in the reaction. The term protecting group may also include a polymer resin having functional groups. DOTA may be used in process step (c) in the free acid form, as an anhydride or as an activated ester, e.g. with N-hydroxysuccinimide.
The complexation with the radionuclide may be performed at room temperature in accordance with methods known in the art, e.g. by reacting an uncomplexed compound of formula I with a salt yielding the desired radionuclide.
Preferably the complexation of the uncomplexed compound of formula I with the radionuclide-yielding salt is effected at a temperature of from 60° to 120° C., more preferably from 80 to 100° C. When the complexation is performed at a temperature ≧100° C., it may be effected in an autoclave. The complexation under heating may conveniently be carried out for a short time period, e.g. from 10 to 20 minutes. When the radionuclide is
90
Y, the preferred
90
Y-yielding salt is
90
YCl
3
.
The above mentioned reactions may conveniently be effected under conditions avoiding trace metal contamination. Preferably distilled de-ionized water, ultrapure reagents, no carrier-added radioactivity etc. are used to reduce the effects of trace metal.
The compounds of formula I, when complexed with a radionuclide, exhibit pharmaceutical activity and are therefore useful as a radiopharmaceutical for the in vivo treatment of somatostatin receptor positive tumors and metastases as indicated by standard tests.
In particular, the compounds of formula I possess affinity for somatostatin receptors which can be assessed in vitro in binding assays performed as disclosed by J. C. Reubi, Life Sc. 36, 1829 (1985) and by C. Bruns et al. in Biochem. J., 265, 39 (1990).
It is observed that the compounds of formula I, e.g. a compound of formula I complexed with
90
Y or
161
Tb, bind with a good affinity and specificity to somatostatin receptors with pK
D
, values of from about 8.0 to 10.0.
Compound of Example 1 binds with high affinity to somatostatin receptors expressed in rat cortex or AR42J pancreatic tumor cells: it has a pKi of 8.9±0.1 using [
125
I] [Tyr
3
]-octreotide as specific ligand. Compound of Example 2 is a somatostatin receptor specific ligand that can be displaced from the somatostatin receptors by octreotide: pIC
50
=9.0±0.3.
The affinity of the complexed compounds of formula I for somatostatin receptors can also be shown by in vivo testing, according to standard test methods, e.g. as disclosed in GB-A-2, 225,579. For example, in one trial, the compound of Example 2 gives a significant tumor accumulation 2 hours following i.p. injection at a dose of 5 &mgr;Ci into mice bearing an exocrine pancreatic tumor: 9.05±0.61% ID/g present in the somatostatin receptor positive tumor whereas significantly less radioactivity is accumulated in somatostatin receptor positive normal tissues, e.g. in the pancreas it amounts 1.52±0.08% ID/g. By % ID/g is meant the percentage of the injected radioactivity dose per g tissue. Not only does Compound of Example 2 provide 24 hours after inject

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