# US 10,869,942 B2 · Method

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- Number: US 10,869,942 B2
- Document ID: US10869942B2
- Status: Granted
- Kind: B2
- Application number: 15/771,152
- Filed: 2016-10-26
- Published: 2018-11-01
- Granted: 2020-12-22
- Earliest claimed: 2015-10-26
- Assignees: Norsk Medisinsk Syklotronsenter AS
- Applicants: Norsk Medisinsk Syklotronsenter AS
- Inventors: Dag Erlend Olberg; Anders Svadberg
- Web page: https://patentgrep.com/patent/US10869942B2

## CPC

- A61K 51/0455: {having six-membered rings with one nitrogen as the only ring hetero atom}
- A61K 51/0497: {conjugates with a carrier being an organic compounds}
- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- C07B 59/002: {Heterocyclic compounds}
- C07B 59/008: {Peptides; Proteins}
- C07D 213/61: Halogen atoms or nitro radicals
- C07D 213/65: attached in position 3 or 5
- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 213/80: in position 3
- C07D 213/803: Processes of preparation
- C07D 213/82: in position 3
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- 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)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to new and improved methods of synthesizing radiolabelling agents which can be used to label biomolecules for use as radiopharmaceuticals. It further relates to certain novel radiolabelling agents and their use in such methods. PET imaging methods and methods of diagnosis employing such radiolabelling agents form a further aspect of the invention.

## Claims

### Claim 1

A radiofluorination process comprising:
(a) providing a solid stationary phase which comprises a polymeric anion-exchange resin having bound thereto [18F]fluoride anions; and
(b) contacting said solid stationary phase with a non-aqueous solution comprising a precursor compound of formula (I):
and a solvent selected from acetonitrile, tent-butanol, dimethylformamide, dimethylsulphoxide, dimethylacetamide, tetrahydrofuran, dioxan, 1,2-dimethoxyethane, sulpholane, N-methylpyrolidinone, or mixtures thereof, or an ionic liquid, optionally in the presence of an organic non-nucleophilic base,
whereby to produce a radiofluorinated compound of formula (II):
wherein: in formula (I), L is a positively charged leaving group; and in formulae (I) and (II), R is a group of the formula:
wherein R′ is an electron-withdrawing group,
wherein the radiofluorination process is performed at a temperature of from 10° C. to 25° C., and wherein the stationary phase is not contacted with a phase transfer catalyst during step (b).

### Claim 2 (depends on 1)

The process of claim 1, wherein in step (b) the solid stationary phase is contacted with the non-aqueous solution of the precursor compound of formula (I) in the presence of an organic non-nucleophilic base.

### Claim 3 (depends on 1)

The process of claim 1, wherein R is

### Claim 4 (depends on 3)

The process of claim 3, wherein R′ is —CF3, —CH2CF3, —CH(CF3)2, —C(CF3)3, or
where n is an integer from 1 to 5 and each Z is independently —F, —Cl, —NO2, or —CN.

### Claim 5 (depends on 1)

The process of claim 1, wherein R is
wherein n is an integer from 1 to 5 and each Z is independently —F, −Cl, —NO2, or —CN. CN.

### Claim 6 (depends on 1)

The process of claim 1, wherein the precursor compound of formula (I) is a compound of formula (Ill):
wherein L is a positively charged leaving group, n is an integer from 1 to 5 and each Z is independently—F, —Cl, —NO2, or —CN.

### Claim 7 (depends on 1)

The process of claim 1, wherein the precursor compound of formula (I) is a compound of general formula (P):
and wherein L and R′ in said compound of general formula (Is) are selected such that said precursor compound is one of compounds (1) to (21):
R’
L
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21).

### Claim 8 (depends on 1)

The process of claim 1, wherein R is

### Claim 9 (depends on 1)

The process of claim 1, wherein the precursor compound of formula (I) is in the form of a trifluoromethanesulphonate salt.

### Claim 10 (depends on 1)

The process of claim 1, further comprising reacting the compound of formula (II) with a compound of formula (III):
H2N-biomolecule (III)
to give a radiolabelled biomolecule of formula (IV):

### Claim 11 (depends on 10)

The process of claim 10, wherein the biomolecule is a peptide, protein, hormone, oligonucleotide, or antibody fragment.

### Claim 12 (depends on 10)

The process of claim 10, wherein the biomolecule is a peptide selected from somatostatin analogues, bombesin, vasoactive intestinal peptide, chemotactic peptide analogues, α-melanocyte stimulating hormone, urea-based PSMA inhibitors, neurotensin, Arg-Gly-Asp peptide and its analogues, human pro-insulin connecting peptide, endothelin, angiotensin and formyl-norleucyl-leucyl-phenylalanyl-norleucyl-tyrosyl-lysine.

### Claim 13 (depends on 10)

The process of claim 10, wherein the biomolecule comprises the fragment:

### Claim 14 (depends on 10)

The process of claim 10, wherein the biomolecule is a peptide of formula (V):
wherein X7 is either —NH2 or
wherein a is an integer of from 1 to 10.

### Claim 15 (depends on 10)

The process of claim 10, wherein the biomolecule is an aminooxy- or hydrazine-modified peptide.

### Claim 16 (depends on 10)

The process of claim 10, wherein the biomolecule is