US 10,377,701 B2Granted

Methods for multi-dose synthesis of [F-18]FDDNP for clinical settings

AssigneeThe Regents of the University of California

InventorsNagichettiar Satyamurthy, Jie Liu, Jorge R. Barrio

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Abstract

A method of manufacturing 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)-malononitrile ([F-18]FDDNP) utilizes a semi-automated module that is used to perform fluorination, pre-purification, separation, product extraction, and formulation. The method is able to produce [F-18]FDDNP with high yields and ready for human administration under existing FDA regulations, and without the need for hazardous organic solvents such as dichloromethane (DCM), methanol (MeOH), and tetrahydrofuran (THF). The method also improves the speed with which [F-18]FDDNP can be synthesized with the method being able to generate a final product within about 90 to 100 minutes. This synthesis method is easily adaptable to FDA registered and approved automated synthesis systems.

Claims13

Dependent claims

A method of manufacturing 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)-malononitrile ([F-18]FDDNP) comprising:

trapping [F-18]fluoride ion in a resin cartridge;
eluting the [F-18]fluoride ion into a reaction vessel having a cryptand solution contained therein by passing a potassium salt solution followed by water through the resin cartridge, wherein a [F-18]fluoride/cryptand complex is formed therein;
subjecting the [F-18]fluoride/cryptand complex to multiple rounds of azeotropic evaporation with anhydrous acetonitrile to form dried [F-18]fluoride ion/cryptand complex residue in the reaction vessel;
reacting the dried [F-18]fluoride ion/cryptand complex with tosyloxy precursor 2-{[6-(2,2-dicyano-1-methylvinyl)-2-naphthyl](methyl)amino}ethyl-4-methylbenzenesulfonate (DDNPTs) in anhydrous acetonitrile to form a reaction product;
passing the reaction product through an alumina cartridge and into an injection vessel;
injecting the reaction product contained in the injection vessel to an HPLC column;
collecting a fraction containing [F-18]FDDNP from the HPLC column in a dilution vessel;
diluting the collected [F-18]FDDNP contained in the dilution vessel with water;
passing the diluted [F-18]FDDNP through a solid-phase extraction cartridge and eluting [F-18]FDDNP with ethanol;
and
diluting the [F-18]FDDNP contained in ethanol with saline and human serum albumin to form a final product.

8 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/807,306Filed 8 Nov 2017 · us provisional application
Priority: 8 Nov 2016
Published: US 2018/0127355 A110 May 2018
Granted: 13 Aug 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07C 253/30
Preparation of carboxylic acid nitriles: by reactions not involving the formation of cyano groups
C07B 59/001
Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se: acyclic or carbocyclic compounds
C07C 253/34
Separation; Purification; Stabilisation; Use of additives: separation; Purification
C07C 255/34
Having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring: with cyano groups…