Radiotracer compositions and methods

Patent metadata

Field	Value
Publication number	US-11311636-B2
Application number	US-201916375223-A
Country	US
Kind code	B2
Filing date	Apr 4, 2019
Priority date	Dec 18, 2013
Publication date	Apr 26, 2022
Grant date	Apr 26, 2022

Abstract

The present invention relates to the field of radiopharmaceuticals for in vivo imaging, in particular to radiotracer compositions which comprises 18F-labelled c-Met binding peptides. The invention provides said compositions, as well as associated automated methods of preparation and cassettes.

First claim

The invention claimed is:

1. A method of preparation of the radiopharmaceutical composition comprising:
(A) reacting a first non-radioactive precursor with [ 18 F]-fluoride to give [ 18 F]-fluorobenzaldehyde in a single-use cassette comprising:
(i) a first non-radioactive precursor, that reacts with [ 18 F]-fluoride to give [ 18 F]-fluorobenzaldehyde, the first non-radioactive precursor having the formula I:

(ii) a second non-radioactive precursor of Formula III:

wherein C a , C b , C c , and C d in Formula III are each cysteine residues and wherein C a and C b together and C c and C d together are cyclized to form two separate disulfide bonds;
(iii) a reverse phase solid phase extraction column;
(iv) a supply of the radioprotectant, wherein the radioprotectant is ascorbic acid, para-aminobenzoic acid, or gentisic acid;
(v) a reaction vessel;
(vi) at least one suitable solvent, wherein the at least one suitable solvent comprises aqueous acetonitrile of 5 to 25% v/v acetonitrile;

(B) reacting the [ 18 F]-fluorobenzaldehyde from step (A) with the second non-radioactive precursor to give a radiotracer of Formula II in a crude radiotracer solution:

 wherein C a , C b , C c , C d in Formula II are each cysteine residues such that residues C a and C b as well as C c and C d are cyclized to form two separate disulfide bonds;
(C) adding said radioprotectant to the crude radiotracer solution from step (B) to form a second radiotracer solution, wherein the second radiotracer solution comprises said radiotracer of Formula II and said radioprotectant in aqueous acetonitrile of 5 to 25% v/v acetonitrile;
(D) purifying the second radiotracer solution from step (C) using said reverse phase solid phase extraction column to give a purified [ 18 F]-radiotracer solution;
(E) optionally diluting the purified [ 18 F]-radiotracer from step (D) with a biocompatible carrier;
(F) filtering the optionally diluted purified [ 18 F]-radiotracer solution from step (E) to give said radiopharmaceutical composition;

wherein said cassette fits removably and interchangeably onto an automated synthesizer apparatus and at least steps (A)-(D) are carried out in the automated synthesizer apparatus.

2. The method of claim 1 , where the steps (A)-(F) are carried out in the automated synthesizer apparatus.

3. The method of claim 1 , where the second radiotracer solution of step (C) further comprises 0.5 to 5% v/v ethanol.

4. The method of claim 1 , where the purification step (D) is carried out as follows:
(i) passing the purified [ 18 F]-radiotracer solution from step (D) through said reverse phase SPE cartridge, wherein the [ 18 F]-radiotracer of Formula II is retained on said SPE cartridge;
(ii) washing the SPE cartridge from step (i) one or more times with a wash solution which comprises an aqueous acetonitrile solution of said radioprotectant of 15 to 25% v/v acetonitrile content;
(iii) washing the SPE cartridge from step (ii) one or more times with water or aqueous buffer solution;
(iv) eluting the washed SPE cartridge of step (ii) or (iii) with an elution solvent which comprises said radioprotectant in an aqueous ethanol solution having an ethanol content of 35 to 80% v/v,

wherein the eluent comprises purified radiotracer in said elution solvent.

5. The method of claim 1 , wherein the SPE cartridge is a C 18 SPE cartridge.

6. The method of claim 5 , where the elution solvent of step (iv) comprises 40-60% v/v aqueous ethanol.

7. The method of claim 5 , which further comprises:
(G) dispensing the [ 18 F]-radiotracer radiopharmaceutical composition of step (F) into one or more syringes.

8. A single use cassette comprising:
a first non-radioactive precursor, that reacts with [ 18 F]-fluoride to give [ 18 F]-fluorobenzaldehyde, the first non-radioactive precursor having the formula I:

a second non-radioactive precursor of Formula III:

 wherein C a , C b , C c , and C d in Formula III are each cyssteine residues and wherein C a and C b together and C c and C d together are cyclized to form two separate disulfide bonds;
a reverse phase solid phase extraction column;
a supply of radioprotectant, wherein the radioprotectant is ascorbic acid, para-aminobenzoic acid, or gentisic acid;
a reaction vessel; and
at least one suitable solvent, wherein the at least one suitable solvent comprises aqueous acetonitrile of 5 to 25% v/v acetonitrile.

Assignees

• Ge Healthcare Ltd

Inventors

• Engell Torgrim
• Getvoldsen Gareth Simon
• Meijer Andreas Richard
• Khan Imtiaz Ahmed
• Mcrobbie Graeme
• Nairne Robert James

Classifications

• A61K51/088 Primary

  conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10) · CPC title

• A61K51/04

  Organic compounds · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07B59/008

  Peptides; Proteins · CPC title