# US 2021/0402016 A1 · Radiolabeled bombesin-derived compounds for in vivo imaging of gastrin-releasing peptide receptor (grpr) and treatment of grpr-related disorders

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- Number: US 2021/0402016 A1
- Document ID: US20210402016A1
- Status: Published application
- Kind: A1
- Application number: 17/293,455
- Filed: 2019-11-13
- Published: 2021-12-30
- Earliest claimed: 2018-11-13
- Assignees: Provincial Health Services Authority
- Applicants: Provincial Health Services Authority
- Inventors: Francois Benard; Kuo-Shyan Lin; Etienne Rousseau; Zhengxing Zhang; Joseph Lau; lvica Bratanovic; Jutta Zeisler
- Web page: https://patentgrep.com/patent/US20210402016A1

## CPC

- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- C07K 7/086: {Bombesin; Related peptides (having more than 20 amino acids C07K14/57572)}
- 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)
- 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)

## Abstract

There is provided bombesin-derived compounds of Formula Ia (RX-L-Xaa1-Gln-Trp-Ala-Val-Xaa2-His-Xaa3-ψ-Xaa4-NH2). RX comprises a radionuclide chelator or a trifluoroborate-containing prosthetic group. L is a linker. Xaa1 is D-Phe, Cpa (4-chlorophenylalanine), D-Cpa, Tpi (2,3,4,9-tetrahydro-1H-pyrido[3,4b]indol-3-carboxylic acid), D-Tpi, Nal (naphthylalanine), or D-Nal. Xaa2 is Gly, N-methyl-Gly or D-Ala. Xaa3 is Leu, Pro, D-Pro, or Phe. Xaa4 is Pro, Phe, Tac (thiazolidine-4-carboxylic acid), Nle (norleucine), 4-oxa-L-Pro (oxazolidine-4-carboxylic acid). The symbol ψ represents a reduced peptide bond between Xaa3 and Xaa4 in which ψ is CH2—N when Xaa4 is Pro, Tac or 4-oxa-L-Pro, or ψ is CH2N(R) when Xaa4 is Phe or Nle wherein R is H or C1-C5 linear or branched alkyl. There is also provided the use of such compounds as imaging agents or therapeutic agents.

## Claims

### Claim 1

A compound of Formula Ia
RX-L-Xaa1-Gln-Trp-Ala-Val-Xaa2-His-Xaa3-ψ-Xaa4-NH2 (Ia)
wherein:
RX comprises a radionuclide chelator or a trifluoroborate-containing prosthetic group;
L is a linker;
Xaai is D-Phe, Cpa (4-chlorophenylalanine), D-Cpa, Tpi (2,3,4,9-tetrahydro-1H-pyrido[3,4b]indol-3-carboxylic acid), D-Tpi, Nal (naphthylalanine), or D-Nal;
Xaa2 is Gly, N-methyl-Gly or D-Ala;
Xaa3 is Leu, Pro, D-Pro, or Phe;
Xaa4 is Pro, Phe, Tac (thiazolidine-4-carboxylic acid), Nle (norleucine), 4-oxa-L-Pro (oxazolidine-4-carboxylic acid); and
ψ represents a reduced peptide bond between Xaa3 and Xaa4 in which ψ is
when Xaa4 is Pro, Tac or 4-oxa-L-Pro, or W is —CH2N(R)— when Xaa4 is Phe or Nle wherein R is H or C1-C5 linear or branched alkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein RX comprises the radionuclide chelator.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the radionuclide chelator is selected from the group consisting of: DOTA and derivatives; DOTAGA; NOTA; NODAGA; NODASA; CB-DO2A; 3p-C-DEPA; TCMC; DO3A; DTPA and DTPA analogues optionally selected from CHX-A″-DTPA and 1B4M-DTPA; TETA; NOPO; Me-3,2-HOPO; CB-TE1A1P; CB-TE2P; MM-TE2A; DM-TE2A; sarcophagine and sarcophagine derivatives optionally selected from SarAr, SarAr-NCS, diamSar, AmBaSar, and BaBaSar; TRAP; AAZTA; DATA and DATA derivatives; H2-macropa or a derivative thereof; H2dedpa, H4octapa, H4py4pa, H4Pypa, H2azapa, H5decapa, and other picolinic acid derivatives; CP256; PCTA; C-NETA; C-NE3TA; HBED; SHBED; BCPA; CP256; YM103; desferrioxamine (DFO) and DFO derivatives; H6phospa; a trithiol chelate; mercaptoacetyl; hydrazinonicotinamide; dimercaptosuccinic acid; 1,2-ethylenediylbis-L-cysteine diethyl ester; methylenediphosphonate;
hexamethylpropyleneamineoxime; and hexakis(methoxy isobutyl isonitrile).

### Claim 4 (depends on 2)

The compound of claim 2, wherein the radionuclide chelator is selected from DOTA and DOTA derivatives.

### Claim 5 (depends on 2)

The compound of any one of claim 2, wherein RX further comprises a radiometal, a radionuclide-bound metal, or a radionuclide-bound metal-containing prosthetic group, and wherein the radiometal, the radionuclide-bound metal, or the radionuclide-bound metal-containing prosthetic group is chelated to the radionuclide-chelator complex.

### Claim 6 (depends on 5)

The compound of claim 5, wherein the radiometal, the radionuclide-bound metal, or the radionuclide-bound metal-containing prosthetic group is: 68Ga, 61Cu, 64Cu, 67Cu, 67Ga 111In, 44Sc, 86Y, 89Zr, 90Nb, 177Lu, 117mSn, 165Er, 90Y, 227Th, 225Ac, 213Bi, 212Bi, 72As, 77As, 211At, 203Pb, 212Pb, 47Sc, 166Ho, 188Re, 186Re, 149Pm, 159Gd, 105Rh, 109Pd, 198Au, 199Au, 175Yb, 142Pr, 114mIn, 94mTc, 99mTc, 149Tb, 152Tb, 155Tb, 161Tb, or [18F]AlF.

### Claim 7 (depends on 5)

The compound of claim 5, wherein the radiometal, the radionuclide-bound metal, or the radionuclide-bound metal-containing prosthetic group is: 68Ga, 61Cu, 64Cu, 67Cu, 67Ga, 111In, 44Sc, 86Y, 177Lu, 90Y, 149Tb, 152Tb, 155Tb, 161Tb, 225Ac, 213Bi, or 212Bi.

### Claim 8 (depends on 1)

The compound of claim 1, wherein RX comprises one or more than one trifluoroborate-containing prosthetic group.

### Claim 9 (depends on 8)

The compound of claim 8, wherein RX comprises one or more than one R1R2BF3 group, wherein:
each R1 is independently
wherein each R3 is independently absent,
and
each R2BF3 is independently:
wherein each R4 is independently a C1-C5 linear or branched alkyl group and each R5 is independently a C1-C5 linear or branched alkyl group,
in which the R in each pyridine substituted —OR, —SR, —NR—, —NHR or —NR2 is independently a branched or linear C1-C5 alkyl.

### Claim 10 (depends on 8)

The compound of claim 8, wherein RX comprises one or more than one R1R2BF3, wherein:
each R1 is independently
wherein each R3 is independently absent,
and
each R2BF3 is independently:
wherein each R4 is independently a C1-C5 linear or branched alkyl group and each R5 is independently a C1-C5 linear or branched alkyl group,
in which the R in each pyridine substituted —OR, —SR, —NR—, —NHR or —NR2 is independently a branched or linear C1-C5 alkyl.

### Claim 11 (depends on 8)

The compound of claim 8, wherein the RX comprises a single R1R2BF3 group.

### Claim 12 (depends on 8)

The compound of claim 8, wherein the RX comprises two R1R2BF3 groups.

### Claim 13 (depends on 8)

The compound of claim 8, wherein the trifluoroborate-containing prosthetic group comprises 18F.

### Claim 14 (depends on 8)

The compound of claim 8, wherein the linker is a peptide linker (Xaa5)1-4, wherein each Xaa5 is independently a proteinogenic or non-proteinogenic amino acid residue.

### Claim 15 (depends on 1)

The compound of claim 1, wherein the linker is a peptide linker (Xaa5)1-4, wherein each Xaa5 is independently a proteinogenic amino acid residue or is a non-proteinogenic amino acid residue, wherein each peptide backbone amino group is independently optionally methylated, and wherein each non-proteinogenic amino acid residue is independently selected from the group consisting of a D-amino acid of a proteinogenic amino acid, Nε, Nε, Nε-trimethyl-lysine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), ornithine (Orn), homoarginine (hArg), 2-amino-4-guanidinobutyric acid (Agb), 2-amino-3-guanidinopropionic acid (Agp), 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp), (3-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminononanoic acid, 10-aminodecanoic acid, 2-aminooctanoic acid, 2-aminoadipic acid (2-Aad), 3-aminoadipic acid (3-Aad), cysteic acid, tranexamic acid, p-aminomethylaniline-diglycolic acid (pABzA-DIG), 4-amino-i-carboxymethyl-piperidine (Pip), NH2(CH2)2O(CH2)2C(O)OH, NH2(CH2)2[O(CH2)2]2C(O)OH (dPEG2), NH2(CH2)2[O(CH2)2]3C(O)OH, NH2(CH2)2[O(CH2)2]4C(O)OH, NH2(CH2)2[O(CH2)2]5C(O)OH, and NH2(CH2)2[O(CH2)2]6C(O)OH.

### Claim 16 (depends on 1)

The compound of claim 1, wherein the linker is p-aminomethylaniline-diglycolic acid (pABzA-DIG), 4-amino-(1-carboxymethyl)piperidine (Pip), 9-amino-4,7-dioxanonanoic acid (dPEG2) or 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp).

### Claim 17

(canceled)

### Claim 18 (depends on 1)

The compound of claim 1, wherein: Xaa1 is D-Phe; and/or Xaa2 is Gly; and/or Xaa3 is Leu; and/or Xaa4 is Pro, Tac or 4-oxa-L-Pro.

### Claim 19

(canceled)

### Claim 20

(canceled)

### Claim 21

(canceled)

### Claim 22

(canceled)

### Claim 23 (depends on 1)

The compound of claim 1, wherein Xaa1 is D-Phe, Xaa2 is Gly, Xaa3 is Leu, and Xaa4 is Pro.

### Claim 24

A compound, the compound having one of the following chemical structure or a salt or solvate thereof, optionally chelated with radionuclide X:

### Claim 25

(canceled)

### Claim 26 (depends on 24)

The compound of claim 24, where X is: 68Ga, 64Cu, 67Cu, 67Ga, 111In, 177Lu, 90Y, or 225Ac, optionally wherein X is 68Ga or 177Lu.

### Claim 27

(canceled)