# US 7,611,692 B2 · Gastrin releasing peptide compounds

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- Number: US 7,611,692 B2
- Document ID: US7611692B2
- Status: Granted
- Kind: B2
- Application number: 10/828,925
- Filed: 2004-04-20
- Published: 2004-12-16
- Granted: 2009-11-03
- Earliest claimed: 2003-01-13
- Assignees: Bracco Imaging S.P.A.
- Inventors: Enrico Cappelletti; Luciano Lattuada; Karen E. Linder; Edmund Marinelli; Palaniappa Nanjappan; Natarajan Raju; Kondareddiar Ramalingam; Rolf E. Swenson; Michael Tweedle
- Web page: https://patentgrep.com/patent/US7611692B2

## CPC

- C07K 7/086: {Bombesin; Related peptides (having more than 20 amino acids C07K14/57572)}
- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- A61P 35/00: Antineoplastic agents
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

New and improved compounds for use in diagnostic imaging or therapy having the formula M—N—O—P—G, wherein M is an optical label or a metal chelator (in the form complexed with a metal radionuclide or not), N—O—P is the linker, and G is the GRP receptor targeting peptide. Methods for imaging a patient and/or providing radiotherapy or phototherapy to a patient using the compounds of the invention are also provided. Methods and kits for preparing a diagnostic imaging agent from the compound is further provided. Methods and kits for preparing a radiotherapeutic agent are further provided.

## Claims

### Claim 1

A compound of the general formula:
M—N—O—P—G
wherein
M is an optical label or a metal chelator optionally complexed with a radionuclide;
N is absent, an alpha amino acid, a non-alpha amino acid with a cyclic group or other linking group;
O is an alpha amino acid or a non-alpha amino acid with a cyclic group;
P is absent, an alpha amino acid, a non-alpha amino acid with a cyclic group, or other linking group; and
G is a GRP receptor targeting peptide selected from the group consisting of QWAVGHLM-OH (SEQ ID NO: 1), QWAVGHLM-NH2 (SEQ ID NO: 1), QWAVGHFL-NH2 (SEQ ID NO: 11), QRLGNQWAVGHLM-NH2 (SEQ ID NO: 3), QRYGNQWAVGHLM-NH2 (SEQ ID NO: 4), QKYGNQWAVGHLM-NH2 (SEQ ID NO: 5), QWAVGHL-NH-Pentyl (SEQ ID NO: 6), QWSVaHLM-NH2 (SEQ ID NO: 7), QWAVGHLL-NH2 (SEQ ID NO: 8), QWAV-Bala-HF-Nle-NH2 (SEQ ID NO: 9), QWAGHFL-NH2 (SEQ ID NO: 10), LWAVGSFM-NH2 (SEQ ID NO: 12), HWAVGHLM-NH2 (SEQ ID NO: 13), LWATGHFM-NH2 (SEQ ID NO: 17), LWAVGSFM-NH2 (SEQ ID NO: 12), EWAVGHLM-NH2 (SEQ ID NO: 2), QWAVaHLM-NH2 (SEQ ID NO: 15), QWAVGHFM-NH2 (SEQ ID NO: 14), Nme-QWAVGHLM-NH2 (SEQ ID NO: 1), Q-Ψ[CSNH]WAVGHLM-NH2 (SEQ ID NO: 1), Q-Ψ[CH2NH]-WAVGHLM-NH2 (SEQ ID NO: 1), Q-Ψ[CH═CH]WAVGHLM-NH2 (SEQ ID NO: 1), α-MeQWAVGHLM-NH2 (SEQ ID NO: 24), QNme-WAVGHLM-NH2 (SEQ ID NO: 29), QW-Ψ[CSNH]-AVGHLM-NH2 (SEQ ID NO: 1), QW-Ψ[CH2NH]-AVGHLM-NH2 (SEQ ID NO: 1), QW-Ψ[CH═CH]-AVGHLM-NH2 (SEQ ID NO: 1), Q-α-Me-WAVGHLM-NH2 (SEQ ID NO: 30), QW-Nme-AVGHLM-NH2 (SEQ ID No: 31), QWA=Ψ[CSNH]-VGHLM-NH2 (SEQ ID NO: 1), QWA-Ψ[CH2NH]-VGHLM-NH2 (SEQ ID No: 1), QW-Aib-VGHLM-NH2 (SEQ ID NO: 1), QWAV-Sar-HLM-NH2 (SEQ ID No: 32), QWAVG-Ψ[CSNH]-HLM-NH2 (SEQ ID NO: 1), QWAVG-Ψ[CH═CH]-HLM-NH2 (SEQ ID NO: 1), QWAV-Dala-HLM-NH2 (SEQ ID NO: 15), QWAVG-Nme-His-LM-NH2 (SEQ ID NO: 33), QWAVG-H-Ψ[CSNH]-L-M-NH2 (SEQ ID NO: 1), QWAVG-H-Ψ[CH2NH]-LM-NH2 (SEQ ID NO: 1), QWAVGH-Ψ[CH═CH]-LM-NH2 (SEQ ID NO: 1), QWAVG-α-Me-HLM-NH2 (SEQ ID NO: 34), QWAVGH-Nme-LM-NH2 (SEQ ID NO: 35), and QWAVGH-α-MeLM-NH2 (SEQ ID NO: 28),
wherein at least one of N, O or P is a non-alpha amino acid with a cyclic group and wherein the other linking group of N or P is selected from the group consisting of one or more amino acids, a hydrocarbon chain of the formula R1—(CH2)n—R2 or a combination thereof, wherein n is 0-10, R1 is selected from the group consisting of H2N—, HS— and —COOH; and R2 is COOH.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the non-alpha amino acid with a cyclic group is selected from the group consisting of:
4-aminobenzoic acid;
4-aminomethyl benzoic acid;
trans-4-aminomethylcyclohexane carboxylic acid;
4-(2-aminoethoxy)benzoic acid;
isonipecotic acid;
2-aminomethylbenzoic acid;
4-amino-3-nitrobenzoic acid;
4-(3-carboxymethyl-2-keto-1-benzimidazolyl)-piperidine;
6-(piperazin-1-yl)-4-(3H)-quinazolinone-3-acetic acid;
(2s,5s)-5-amino-1,2,4,5,6,7-hexahydro-4-oxo-azepino[3,2,1-hi]indole-2-carboxylic acid,
(4S,7R)-4-amino-6-aza-5-oxo-9-thiabicyclo[4.3.0]nonane-7-carboxylic acid;
3-carboxymethyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one;
N1-piperazineacetic acid;
N-4-aminoethyl-N-1-acetic acid;
(3S)-3-amino-1-carboxymethylcaprolactam; and
(2S,6S,9)-6-amino-2-carboxymethyl-3,8-diazabicyclo-[4,3,0]-nonane-1,4-dione;
1-naphthylalanine;
3′-aminomethyl-biphenyl-3-carboxylic acid;
4-aminomethylphenoxyacetic acid;
4-aminophenylacetic acid;
4-phenoxy;
3-aminomethylbenzoic acid;
4-aminomethyl-3-methoxybenzoic acid;
4-hydrazinobenzoyl;
6-aminonicotinic acid;
4-amino-2′-methylbiphenyl-4-carboxylic acid;
Terephthalic acid;
3-aminobenzoic acid;
6-aminonaphthoic acid;
3-amino-3-deoxycholoic acid;
3-methoxy-4-aminobenzoic acid;
3-chloro-4-aminobenzoic acid; and
3-hydroxy-4-aminobenzoic acid.

### Claim 3 (depends on 1)

The compound of claim 1, wherein M is selected from the group consisting of: DTPA, DOTA, DO3A, HPDO3A, EDTA, and TETA.

### Claim 4 (depends on 1)

The compound of claim 1, wherein M is selected from the group consisting of EHPG, 5-Cl-EHPG, 5-Br-EHPG, 5-Me-EHPG, 5-t-Bu-EHPG, and 5-sec-Bu-EHPG.

### Claim 5 (depends on 1)

The compound of claim 1, wherein M is selected from the group consisting of benzodiethylenetriamine pentaacetic acid (benzo-DTPA), dibenzo-DTPA, phenyl-DTPA, diphenyl-DTPA, benzyl-DTPA, and dibenzyl DTPA.

### Claim 6 (depends on 1)

The compound of claim 1, wherein M is selected from the group consisting of HBED.

### Claim 7 (depends on 1)

The compound of claim 1, wherein M is selected from the group consisting of benzo-DOTA, dibenzo-DOTA, and benzo-NOTA, benzo-TETA, benzo-DOTMA, and benzo-TETMA.

### Claim 8 (depends on 1)

The compound of claim 1, wherein M is selected from the group consisting of 1,3-propylenediaminetetraacetic acid (PDTA) and triethylenetetraaminehexaacetic acid (TTHA); 1,5,10-N,N′,N″-tris(2,3-dihydroxybenzoyl)-tricatecholate (LICAM) and 1,3,5-N,N′,N″-tris(2,3-dihydroxybenzoyl)aminomethylbenzene (MECAM).

### Claim 9 (depends on 1)

The compound of claim 1, selected from the group consisting of:
DO3A-monoamide-G-4-aminobenzoic acid-EWAVGHLM-NH2 (SEQ ID NO: 2);
DO3A-monoamide-G-4-aminobenzoic acid-QWAVGHLM-OH (SEQ ID NO: 1);
DO3A-monoamide-G-4-aminobenzoic acid-(D)-Phe-BBN(7-14);
DO3A-monoamide-G-4-aminobenzoic acid-QRLGNQWAVGHLM-NH2 (SEQ ID NO: 3);
DO3A-monoamide-G-4-aminobenzoic acid-QRYGNQWAVGHLM-NH2 (SEQ ID NO: 4);
DO3A-monoamide-G-4-aminobenzoic acid-QKYGNQWAVGHLM-NH2 (SEQ ID NO: 5);
DO3A-monoamide-G-4-aminobenzoic acid-(D)-Phe-QWAVGHL-NH-Pentyl (SEQ ID NO: 6);
DO3A-monoamide-G-4-aminobenzoic acid-QWSVaHLM-NH2 (SEQ ID NO: 7);
DO3A-monoamide-G-4-aminobenzoic acid-(D)-Phe-QWAVGHLL-NH2 (SEQ ID NO: 8);
DO3A-monoamide-G-4-aminobenzoic acid-(D)-Tyr-QWAV-Bala-HF-Nle-NH2 (SEQ ID NO: 9);
DO3A-monoamide-G-4-aminobenzoic acid-Phe-QWAV-Bala-HF-Nle-NH2 (SEQ ID NO: 9);
DO3A-monoamide-G-4-aminobenzoic acid-QWAGHFL-NH2 (SEQ ID NO: 10);
DO3A-monoamide-G-4-aminobenzoic acid-LWAVGSFM-NH2 (SEQ ID NO: 12);
DO3A-monoamide-G-4-aminobenzoic acid-HWAVGHLM-NH2 (SEQ ID NO: 13);
DO3A-monoamide-G-4-aminobenzoic acid-LWAVGSFM-NH2 (SEQ ID NO: 12);
DO3A-monoamide-G-4-aminobenzoic acid-QWAVGHFM-NH2 (SEQ ID NO: 14);
DO3A-monoamide-G-4-aminobenzoic acid-QWAVGHFL-NH2 (SEQ ID NO: 11);
DO3A-monoamide-4-aminomethylbenzoic acid-L-1-Naphthylalanine-QWAVGHLM-NH2 (SEQ ID NO: 1); and
DO3A-monoamide-G-4-aminobenzoic acid-QWAVGNMeHisLM-NH2 (SEQ ID NO: 16).

### Claim 10 (depends on 1, 2)

The compound of any one of claims 1 or 2, wherein the optical label is selected from the group consisting of organic chromophores, organic fluorophores, light-absorbing compounds, light-reflecting compounds, light-scattering compounds, and bioluminescent molecules.

### Claim 11 (depends on 1)

A method of imaging a patient comprising the steps of:
administering to a subject a diagnostic imaging agent comprising the compound of claim 1 wherein M is a metal chelator complexed with a diagnostic radionuclide, and
imaging said patient.

### Claim 12 (depends on 9)

A method of imaging a patient comprising the steps of:
administering to a patient a diagnostic imaging agent comprising the compound of claim 9, and
imaging said patient.

### Claim 13 (depends on 1)

A method of imaging a patient comprising the steps of:
administering to a patient a diagnostic imaging agent comprising the compound of claim 1, wherein M is an optical label, and
imaging said patient.

### Claim 14 (depends on 1)

A method for preparing a diagnostic imaging agent comprising the step of adding to an injectable medium a substance comprising the compound of claim 1.

### Claim 15 (depends on 1)

A method of treating a patient in need of radiotherapy comprising the step of administering to a patient a radiotherapeutic agent comprising the compound of claim 1 complexed with a therapeutic radionuclide.

### Claim 16 (depends on 1)

A method of preparing a radiotherapeutic agent comprising the step of adding to an injectable medium a substance comprising the compound of claim 1.

### Claim 17

A compound of the general formula:
M—N—O—P—G
wherein
M is DO3A, optionally complexed with a radionuclide;
N is absent, an alpha or non-alpha amino acid or other linking group;
O is an alpha or non-alpha amino acid; and
P is absent, an alpha or non-alpha amino acid or other linking group,
and G is a GRP receptor targeting peptide selected from the group consisting of QWAVGHLM-OH (SEQ ID NO: 1), QWAVGHLM-NH2 (SEQ ID NO: 1), QWAVGHFL-NH2 (SEQ ID NO: 11), QRLGNQWAVGHLM-NH2 (SEQ ID NO: 3), QRYGNQWAVGHLM-NH2 (SEQ ID NO: 4), QKYGNQWAVGHLM-NH2 (SEQ ID NO: 5), QWAVGHL-NH-Pentyl (SEQ ID NO: 6), QWSVaHLM-NH2 (SEQ ID NO: 7), QWAVGHLL-NH2 (SEQ ID NO: 8), QWAV-Bala-HF-Nle-NH2 (SEQ ID NO: 9), QWAGHFL-NH2 (SEQ ID NO: 10), LWAVGSFM-NH2 (SEQ ID NO: 12), HWAVGHLM-NH2 (SEQ ID NO: 13), LWATGHFM-NH2 (SEQ ID NO: 17), LWAVGSFM —NH2 (SEQ ID NO: 12), EWAVGHLM-NH2 (SEQ ID NO: 2), QWAVaHLM —NH2 (SEQ ID NO: 15), QWAVGHFM-NH2 (SEQ ID NO: 14), Nme-QWAVGHLM-NH2 (SEQ ID NO: 1), Q-Ψ[CSNH]WAVGHLM-NH2 (SEQ ID NO: 1), Q-Ψ[CH2NH]-WAVGHLM-NH2 (SEQ ID NO: 1), Q-Ψ[CH═CH]WAVGHLM-NH2 (SEQ ID NO: 1), α-MeQWAVGHLM-NH2 (SEQ ID NO: 24), QNme-WAVGHLM-NH2 (SEQ ID NO: 29), QW-Ψ[CSNH]-AVGHLM-NH2 (SEQ ID NO: 1), QW-Ψ[CH2NH]-AVGHLM-NH2 (SEQ ID NO: 1), QW-Ψ[CH═CH]-AVGHLM-NH2 (SEQ ID NO: 1), Q-α-Me-WAVGHLM-NH2 (SEQ ID NO: 30), QW-Nme-AVGHLM-NH2 (SEQ ID NO: 31), QWA=Ψ[CSNH]-VGHLM-NH2 (SEQ ID NO: 1), QWA-Ψ[CH2NH]-VGHLM-NH2 (SEQ ID NO: 1), QW-Aib-VGHLM-NH2 (SEQ ID NO: 1), QWAV-Sar-HLM-NH2 (SEQ ID NO: 32), QWAVG-Ψ[CSNH]-HLM-NH2 (SEQ ID NO: 1), QWAVG-Ψ[CH═CH]-HLM-NH2 (SEQ ID NO: 1), QWAV-Dala-HLM-NH2 (SEQ ID NO: 15), QWAVG-Nme-His-LM-NH2 (SEQ ID NO: 33), QWAVG-H-Ψ[CSNH]-L-M-NH2 (SEQ ID No: 1), QWAVG-H-Ψ[CH2NH]-LM-NH2 (SEQ ID NO: 1), QWAVGH-Ψ[CH═CH]-LM-NH2 (SEQ ID NO: 1), QWAVG-α-Me-HLM-NH2 (SEQ ID NO: 34), QWAVGH-Nme-LM-NH2 (SEQ ID NO: 35), and QWAVGH-α-MeLM-NH2 (SEQ ID NO: 28),
wherein at least one of N, O or P is 4-aminobenzoic acid and wherein the other linking group of N or P is selected from the group consisting of one or more amino acids, a hydrocarbon chain of the formula R1—(CH2)n—R2 or a combination thereof, wherein n is 0-10, R1 is selected from the group consisting of H2N—, HS— and —COOH; and R2 is COOH.

### Claim 18 (depends on 1)

A method of phototherapy of a patient in need thereof comprising administering to a patient a compound of claim 1 wherein M is an optical label useful in phototherapy.

### Claim 19

A compound selected from the group consisting of:
DO3A-monoamide-G-4-aminobenzoic acid-QWAVaHLM-NH2 (SEQ ID NO: 15),
DO3A-monoamide-G-4-aminobenzoic acid-fQWAVGHLM-NH2 (SEQ ID NO: 1),
DO3A-monoamide-G-4-aminobenzoic acid-fQWAVGHLL-NH2 (SEQ ID NO: 8),
DO3A-monoamide-G-4-aminobenzoic acid-fQWAVGHL-NH-pentyl (SEQ ID NO: 6),
DO3A-monoamide-G-4-aminobenzoic acid-yQWAV-Bala-HFNle-NH2 (SEQ ID NO: 9),
DO3A-monoamide-G-4-aminobenzoic acid-fQWAV-Bala-HFNle-NH2 (SEQ ID NO: 9),
DO3A-monoamide-G-4-aminobenzoic acid-QWAVGHFL-NH2 (SEQ ID NO: 11),
DO3A-monoamide-G-4-aminobenzoic acid-QWAVGNMeHisLM-NH2 (SEQ ID NO: 16),
DO3A-monoamide-G-4-aminobenzoic acid-LWAVGSFM-NH2 (SEQ ID NO: 12),
DO3A-monoamide-G-4-aminobenzoic acid-HWAVGHLM-NH2 (SEQ ID NO: 13),
DO3A-monoamide-G-4-aminobenzoic acid-LWATGHFM-NH2 (SEQ ID NO: 17),
DO3A-monoamide-G-4-aminobenzoic acid-QWAVGHFM-NH2 (SEQ ID NO: 14),
DO3A-monoamide-G-4-aminobenzoic acid-QRLGNQWAVGHLM-NH2 (SEQ ID NO: 3),
DO3A-monoamide-G-4-aminobenzoic acid-QRYGNQWAVGHLM-NH2 (SEQ ID NO: 4),
DO3A-monoamide-G-4-aminobenzoic acid-QKYGNQWAVGHLM-NH2 (SEQ ID NO: 5),
Pglu-Q-Lys(DO3A-monoamide-G-4-aminobenzoic acid)-LGNQWAVGHLM-NH2 (SEQ ID NO: 18).

### Claim 20 (depends on 15)

The method of claim 15 further comprising administering a chemotherapeutic or a monoclonal antibody.

### Claim 21 (depends on 1, 17)

A method for targeting the gastrin releasing peptide receptor (GRP-R) and neuromedin-B receptor (NMB-R), said method comprising administering a compound of any one of claims 1 or 17.

### Claim 22 (depends on 21)

The method of claim 21, wherein N is Gly, O is 4-aminobenzoic acid and P is absent.

### Claim 23

A compound having the following structure:

### Claim 24 (depends on 1)

The compound of claim 1, wherein M is selected from the group consisting of Boa and Cm4pm10d2a.

### Claim 25 (depends on 1)

The compound of claim 1, where M is selected from the group consisting of: N,N-dimethylGly-Ser-Cys;
N,N-dimethylGly-Thr-Cys;
N,N-diethylGly-Ser-Cys;
N,N-dibenzylGly-Ser-Cys;
N,N-dimethylGly-Ser-Cys-Gly;
N,N-dimethylGly-Thr-Cys-Gly;
N,N-diethylGly-Ser-Cys-Gly; and
N,N-dibenzylGly-Ser-Cys-Gly.