# US 2021/0330819 A1 · Design and development of neurokinin-1 receptor-binding agent delivery conjugates

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- Number: US 2021/0330819 A1
- Document ID: US20210330819A1
- Status: Published application
- Kind: A1
- Application number: 17/365,733
- Filed: 2021-07-01
- Published: 2021-10-28
- Earliest claimed: 2014-08-09
- Assignees: Purdue Research Foundation
- Applicants: Purdue Research Foundation
- Inventors: Ananda Kumar Kanduluru; Philip Stewart Low
- Web page: https://patentgrep.com/patent/US20210330819A1

## CPC

- A61K 49/0052: {Small organic molecules (oligomers, polymers, dendrimers A61K49/0054)}
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 38/05: Dipeptides
- A61K 49/0041: {Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal (in vivo G01N)}
- A61K 51/0455: {having six-membered rings with one nitrogen as the only ring hetero atom}
- A61K 51/0459: {having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine}
- A61K 51/0478: {complexes from non-cyclic ligands, e.g. EDTA, MAG3}
- A61K 51/0482: {chelates from cyclic ligands, e.g. DOTA}
- A61K 51/06: Macromolecular compounds {, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules (peptides, proteins, polyamino acids A61K51/08; antibodies A61K51/10)}
- A61K 51/08: Peptides, e.g. proteins {, carriers being peptides, polyamino acids, proteins}
- C07K 14/70571: {for neuromediators, e.g. serotonin receptor, dopamine receptor}
- C09B 11/24: Phthaleins containing amino groups {; Phthalanes; Fluoranes; Phthalides; Rhodamine dyes; Phthaleins having heterocyclic aryl rings; Lactone or lactame forms of triarylmethane dyes}
- C09B 23/0025: {the substituent being bound through an oxygen atom}
- C09B 23/0066: {the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)}
- 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)
- C09B: ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES {, e.g. PIGMENTS}; MORDANTS; LAKES (fermentation or enzyme using processes to synthesise a desired chemical compound C12P)

## Abstract

Neurokinin-1 (NK-1) receptor-binding agent delivery conjugates, compositions comprising NK-1 receptor-binding agent delivery conjugates, and methods for making and administering NK-1 receptor-binding agent delivery conjugates are provided. A conjugate may include an NK-1 receptor-binding moiety, a tinker group containing at least one linker selected from the group of a releasable linker and a spacer linker, and an active agent linked to the linker group. The active agent may be selected from the group of fluorophore-containing compounds, radionuclide-containing compounds, and therapeutic agents for treatment of tumor cells characterized by over-expression of the NK-1 receptor.

## Claims

### Claim at position 1

1-15. (canceled)

### Claim 16

A neurokinin-1 (NK-1) receptor-binding conjugate comprising:
an NK-1 receptor-binding moiety;
an active agent comprising a radionuclide; and
a linker, which links the NK-1 receptor-binding moiety and the active agent, comprises at least one spacer linker, and optionally further comprises a releasable linker.

### Claim 17 (depends on 16)

The NK-1 receptor-binding conjugate of claim 16, wherein the active agent is a radio-imaging agent, an optical imaging agent, a position emission tomography (PET)imaging agent, a magnetic resonance imaging (MRI) contrast agent, a computed tomography (CT) contrast agent, or a fluorescence resonance energy transfer (FRET) imaging agent.

### Claim 18 (depends on 16)

The NK-1 receptor-binding conjugate of claim 16, wherein the active agent comprises a chelator in complex with a radionuclide selected from the group consisting of technetium-99m (99mTc), gallium-68 (68Ga), indium-111 (111In), yttrium-90 (90Y), lutetium-177 (177Lu), zirconium-89 (89Zr), actinium-225 (225Ac), cobalt-60 (60Co), and copper-64 (64Cu).

### Claim 19 (depends on 16)

The NK-1 receptor-binding conjugate of claim 16, wherein the radionuclide is 99mTc or 64Cu.

### Claim 20 (depends on 18)

The NK-1 receptor-binding conjugate of claim 18, wherein the chelator is selected from the group consisting of:
wherein each R is independently H, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted, and wherein one R comprises a heteroatom, which is attached to the linker; X is oxygen, nitrogen, or sulfur, and is attached to the linker; and n is an integer from 1 to 5.

### Claim 21 (depends on 20)

The NK-1 receptor-binding conjugate of claim 20, wherein the heteroatom in R is oxygen, nitrogen or sulfur.

### Claim 22 (depends on 19)

The NK-1 receptor-binding conjugate of claim 19, wherein the chelator is a tripeptide or tetrapeptide.

### Claim 23 (depends on 22)

The NK-1 receptor-binding conjugate of claim 22, wherein the tripeptide has the formula:
wherein each R is independently H, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted, and wherein one R comprises a heteroatom, which is attached to the linker.

### Claim 24 (depends on 23)

The NK-1 receptor-binding conjugate of claim 23, wherein the heteroatom in R is oxygen, nitrogen or sulfur.

### Claim 25 (depends on 18)

The NK-1 receptor-binding conjugate of claim 18, wherein the chelator is selected from the group consisting of:

### Claim 26 (depends on 16)

The NK-1 receptor-binding conjugate of claim 16, wherein the NK-1 receptor-binding moiety comprises a selective NK-1 receptor antagonist or a derivative thereof.

### Claim 27 (depends on 16)

The NK-1 receptor-binding conjugate of claim 16, wherein the NK-1 receptor-binding moiety is selected from the group consisting of:

### Claim 28 (depends on 16)

The NK-1 receptor-binding conjugate of claim 16, wherein the spacer linker comprises amino acids selected from the group consisting of naturally occurring amino acids and stereoisomers thereof.

### Claim 29 (depends on 16)

The NK-1 receptor-binding conjugate of claim 16, wherein the linker comprises dithioalkyloxycarbonyl.

### Claim 30 (depends on 16)

The NK-1 receptor-binding conjugate of claim 16, wherein the linker comprises 3-thiosuccinimid-1-ylalkyloxy.

### Claim 31 (depends on 16)

The NK-1 receptor-binding conjugate of claim 16, wherein the linker comprises 3-cysteinylsuccinimid-1-ylalkyloxy, wherein the cysteinyl is optically active or optically inactive.

### Claim 32 (depends on 16)

The NK-1 receptor-binding conjugate of claim 16, wherein the conjugate is selected from:

### Claim 33 (depends on 16)

A pharmaceutical composition comprising a NK-1 receptor-binding conjugate of claim 16, and a pharmaceutically acceptable carrier, diluent, or excipient.

### Claim 34 (depends on 16)

A method of using a NK-1 receptor-binding conjugate, which method comprises:
(a) administering to a subject an effective amount of the NK-1 receptor-binding conjugate of claim 16, optionally as a pharmaceutical composition comprising the NK-1 receptor-binding conjugate and a pharmaceutically acceptable carrier, diluent, or excipient, and
(b) detecting the radionuclide in the subject.

### Claim 35 (depends on 34)

The method of claim 34, which further comprises diagnosing a disease, locating metastatic disease, detecting disease recurrence, or monitoring response to therapy.

### Claim 36 (depends on 35)

The method of claim 35, which further comprises selecting a patient for cholecystokinin 2 receptor targeted therapy.