Hydrophilic somatostatin analogs

Details Hydrophilic somatostatin analogs Hydrophilic somatostatin analogs

1998-11-19

2002-10-15

Borin, Michael (Department: 1631)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Somatostatin ; related peptides

C530S300000, C530S327000, C530S329000, C514S005200, C514S014800, C514S015800, C424S001110, C424S001690

Reexamination Certificate

active

06465613

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to somatostatin analogs which find use, e.g., in the detection, imaging, or specific targeting of somatostatin receptor-expressing cells, particularly neoplastic cells.
Somatostatin (SRIF) is an endogenous neuropeptide that acts as a regulator of growth hormone (GH) secretion. Somatostatin additionally inhibits the release of other pituitary hormones (i.e., thyrotropin, prolactin) and suppresses both exocrine and endocrine functions of the gastro-entero-pancreatic system. Native human SRIF has the following amino acid sequence (from the amino to carboxy termini): Ala-Gly-c[Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys]
At least five types of somatostatin receptors are known to exist and are expressed on cells in the brain and in peripheral tissues. In addition, somatostatin receptors are present on certain types of tumors, including carcinoids, islet cell tumors, small cell lung tumors, CNS (neuroendocrine) tumors and some thyroid carcinomas. At least some of the biological effects of somatostatin have been associated with the binding of somatostatin to a particular type of receptor (e.g., binding to somatostatin receptor type 5 results in a different biological response than does the binding to somatostatin receptor type 2).
SUMMARY OF THE INVENTION
In general, the invention features novel somatostatin analogs which may be readily detectably labeled, e.g., with a radioactive label. Such analogs are useful for intraoperative tumor localization, and for imaging somatostatin receptor-bearing cells and specifically targeting toxicity (e.g., radioactivity) to such cells.
According, in a first aspect, the invention features a somatostatin analog of the formula: W-X-(A-B)
n
-somatostatin peptide
where A is D-tyrosine, L-tyrosine, D-3-iodotyrosine, L-3-iodotyrosine, D-3,5-diiodotyrosine, L-3,5-diiodotyrosine, D-4-aminophenylalanine, or L-4-aminophenylalanine; B is D-lysine, L-lysine, D-arginine, L-arginine, D- or L-1,3-diaminopropionic acid, D- or L-1,4-diaminobutanoic acid, D-NH
2
—CH(Z)—CO
2
H, or L-NH
2
—CH(Z)—CO
2
H, wherein Z is (CH
2
)
y
NH
2
, wherein y is 1-10; X is A or B; W is absent or is NH
2
(CH
2
)
t
CO, wherein t=2-10; n is 1-10; and each (A-B) may be the same as or different from each other (A-B). In one preferred embodiment, the analog is attached to a detectable label. The detectable label may be toxic (e.g., radioactive) or non-toxic.
In another embodiment of the first aspect of the invention, the analog is indirectly attached to the detectable label. For example, the analog may be attached to a chelating group that is attached to the detectable label.
In another embodiment of the first aspect of the invention, the analog is directly attached to the detectable label.
In another embodiment of the first aspect, the detectable label is an iodine label that is attached to a tyrosine residue or a phenylalanine residue of the analog. The iodine label may be radioactive (e.g., a short-acting radioactive iodine label, such as
123
I (t½=hours) or
131
I (t½=days)). Preferably, the analog includes a tyrosine residue, and the iodotyrosine residue of the analog does not undergo enzymatic deiodination. More preferably, the tyrosine residues is a D-tyrosine residue, and the D-iodotyrosine residue does not undergo enzymatic deiodination.
In other embodiments of the first aspect, the analog has a biological activity that is greater than or equal to the biological activity of the somatostatin peptide of the analog; the analog is used as an anti-neoplastic therapeutic; the analog is in a pharmaceutically acceptable carrier; the analog is used to specifically target an angiogenic blood vessel or a cell thereof; the analog is used for imaging a cell expressing a receptor to which the analog specifically binds; and the analog is used to detect a cell expressing a receptor to which the analog specifically binds (e.g., the analog is used for intraoperative tumor localization).
In a second aspect, the invention features a method for treating or alleviating a neoplasm in an animal that includes the steps of: (a) providing an animal including a somatostatin receptor-bearing neoplastic cell; (b) providing a somatostatin analog having the formula:
W-X-(A-B)
n
-somatostatin peptide
where A is D-tyrosine, L-tyrosine, D-3-iodotyrosine, L-3-iodotyrosine, D-3,5-diiodotyrosine, L-3,5-diiodotyrosine, D-4-aminophenylalanine, or L-4-aminophenylalanine; B is D-lysine, L-lysine, D-arginine, L-arginine, D- or L-1,3-diaminopropionic acid, D- or L-1,4-diaminobutanoic acid, D-NH
2
—CH(Z)—CO
2
H, or L-NH
2
—CH(Z)—CO
2
H, wherein Z is (CH
2
)
y
NH
2
, wherein y is 1-10; X is A or B; W is absent or is NH
2
(CH
2
)
t
CO, wherein t=2-10; n is 1-10; and each (A-B) may be the same as or different from each other (A-B),
where the somatostatin analog specifically binds to the somatostatin receptor; and (c) administering a neoplastic cell growth-arresting amount of the somatostatin analog to the animal. Preferably, the animal is a mammal (e.g., a human).
In a third aspect, the invention features a method for treating or alleviating a neoplasm in an animal that includes the steps of: (a) providing an animal including a somatostatin receptor-bearing neoplastic cell; (b) providing a detectably labeled somatostatin analog, where the detectable label is toxic and the analog has the formula:
W-X-(A-B)
n
-somatostatin peptide
where A is D-tyrosine, L-tyrosine, D-3-iodotyrosine, L-3-iodotyrosine, D-3,5-diiodotyrosine, L-3,5-diiodotyrosine, D-4-aminophenylalanine, or L-4-aminophenylalanine; B is D-lysine, L-lysine, D-arginine, L-arginine, D- or L-1,3-diaminopropionic acid, D- or L-1,4-diaminobutanoic acid, D-NH
2
—CH(Z)—CO
2
H, or L-NH
2
—CH(Z)—CO
2
H, wherein Z is (CH
2
)
y
NH
2
, wherein y is 1-10; X is A or B; W is absent or is NH
2
(CH
2
)
t
CO, wherein t=2-10; n is 1-10; and each (A-B) may be the same as or different from each other (A-B),
where the somatostatin analog specifically binds to the somatostatin receptor; and (c) administering a neoplastic cell growth-arresting amount of the somatostatin analog to the animal. Preferably, the animal is a mammal (e.g., a human).
In a fourth aspect, the invention features a method for imaging a somatostatin receptor-bearing cell in an animal that includes the steps of: (a) providing an animal including a somatostatin receptor-bearing cell; (b) providing a detectably labeled somatostatin analog of the formula:
W-X-(A-B)
n
-somatostatin peptide
where A is D-tyrosine, L-tyrosine, D-3-iodotyrosine, L-3-iodotyrosine, D-3,5-diiodotyrosine, L-3,5-diiodotyrosine, D-4-aminophenylalanine, or L-4-aminophenylalanine; B is D-lysine, L-lysine, D-arginine, L-arginine, D- or L-1,3-diaminopropionic acid, D- or L-1,4-diaminobutanoic acid, D-NH
2
—CH(Z)—CO
2
H, or L-NH
2
—CH(Z)—CO
2
H, wherein Z is (CH
2
)
y
NH
2
, wherein y is 1-10; X is A or B; W is absent or is NH
2
(CH
2
)
t
CO, wherein t=2-10; n is 1-10; and each (A-B) may be the same as or different from each other (A-B),
where the somatostatin analog specifically binds to the somatostatin receptor; and (c) administering the somatostatin analog to the animal, wherein the administration allows for the imaging of the cell. Preferably, the animal is a mammal (e.g., a human).
In a fifth aspect, the invention features a method for detecting, in an animal, a cell that expresses an abnormally high level of a somatostatin receptor that includes the steps of: (a) providing an animal including a cell that expresses an abnormally high level of a somatostatin receptor; (b) providing a detectably labeled somatostatin analog of the formula:
W-X-(A-B)
n
-somatostatin peptide
where A is D-tyrosine, L-tyrosine, D-3-iodotyrosine, L-3-iodotyrosine, D-3,5-diiodotyrosine, L-3,5-diiodotyrosine, D-4-aminophenylalanine, or L-4-aminophenylalanine; B is D-lysine, L-lysine, D-arginine, L-arginine, D- or L-1,3-diaminopropionic acid, D- or L-1,4-diaminobutanoic acid, D-NH
2
—CH(Z)—CO
2
H, or L-NH
2
—CH(Z)—CO
2
H, wherein Z is (CH
2
)
y
NH
2
, wherein y

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