Claims for Patent: 8,936,777

Summary for Patent: 8,936,777

Title:	Methods and apparatus for synthesizing imaging agents, and intermediates thereof
Abstract:	The present invention generally relates to methods and system for the synthesis of imaging agents, and precursors thereof. The methods may exhibit improved yields and may allow for the large-scale synthesis of imaging agents, including imaging agents comprising a radioisotope (e.g., 18F). Various embodiments of the invention may be useful as sensors, diagnostic tools, and the like. In some cases, methods for evaluating perfusion, including myocardial perfusion, are provided. Synthetic methods of the invention have also been incorporated into an automated synthesis unit to prepare and purify imaging agents that comprise a radioisotope. In some embodiments, the present invention provides a novel methods and systems comprising imaging agent 1, including methods of imaging in a subject comprising administering a composition comprising imaging agent 1 to a subject by injection, infusion, or any other known method, and imaging the area of the subject wherein the event of interest is located.
Inventor(s):	Richard R. Cesati, Edward H. Cheesman, Joel Lazewatsky, Heike S. Radeke, Enrico Mongeau, Dianne D. Zdankiewicz, Marybeth Devine
Assignee:	Lantheus Medical Imaging Inc
Application Number:	US13/577,674
Patent Claims:	1. A method of synthesizing an imaging agent comprising the formula: wherein: W is alkyl or heteroalkyl, optionally substituted; R1 is alkyl, optionally substituted; R2 is hydrogen or halide; each R3 can be the same or different and is alkyl optionally substituted with an imaging moiety or heteroalkyl optionally substituted with an imaging moiety; and n is 1, 2, 3, 4, or 5; the method comprising steps of: reacting precursor compounds comprising the formulae: wherein: n is 1, 2, 3, 4, or 5; R1 is alkyl, optionally substituted; R2 is hydrogen or halide; R3 can be the same or different and are alkyl, heteroalkyl, or a carbonyl-containing group, each optionally substituted; R5 is hydroxyl or halide; and R6 is alkyl, heteroalkyl, or a carbonyl-containing group, each optionally substituted; wherein, when R5 is hydroxyl, at least one of R6 and R3 comprises a leaving group; or wherein R5 is halide, at least one of R6 or R3 comprises a hydroxyl, to produce a compound comprising the formula: wherein: W is alkyl or heteroalkyl, optionally substituted; R1 is alkyl, optionally substituted; R2 is hydrogen or halide; each R3 can be the same or different and is alkyl optionally substituted with hydroxyl or heteroalkyl optionally substituted with hydroxyl; wherein at least one R3 comprises hydroxyl; and n is 1, 2, 3, 4, or 5; reacting a compound comprising the formula: wherein: W is alkyl or heteroalkyl, optionally substituted; R1 is alkyl, optionally substituted; R2 is hydrogen or halide; each R3 can be the same or different and is alkyl optionally substituted with hydroxyl or heteroalkyl optionally substituted with hydroxyl; wherein at least one R3 comprises hydroxyl; and n is 1, 2, 3, 4, or 5; with a sulfonate-containing species to produce a sulfonate-containing compound comprising the formula: wherein: W is alkyl or heteroalkyl, optionally substituted; R1 is alkyl, optionally substituted; R2 is hydrogen or halide; each R3 can be the same or different and is alkyl optionally substituted with a sulfonate-containing group or heteroalkyl optionally substituted with a sulfonate-containing group; wherein at least one R3 comprises a sulfonate-containing group; and n is 1, 2, 3, 4, or 5; replacing the sulfonate-containing group of the sulfonate-containing compound with an imaging moiety in the presence of a bicarbonate salt to yield an imaging agent comprising the formula: wherein: W is alkyl or heteroalkyl, optionally substituted; R1 is alkyl, optionally substituted; R2 is hydrogen or halide; each R3 can be the same or different and is alkyl optionally substituted with an imaging moiety or heteroalkyl optionally substituted with an imaging moiety; and n is 1, 2, 3, 4, or 5; provided that at least one imaging moiety is present in the imaging agent. 2. A method of synthesizing a product comprising an 18F-species, comprising reacting a compound comprising the formula: wherein: R1 is alkyl; R2 is hydrogen or halogen; and R3 is alkyl substituted with a sulfonate-containing group, alkoxy substituted with a sulfonate-containing group, or alkoxyalkyl substituted with a sulfonate-containing group; with an 18F-containing species in the presence of a bicarbonate salt to form the product comprising the 18F-species. 3. The method of claim 2, wherein the sulfonate-containing group is mesylate, tosylate, triflate, or 1,2-cyclic sulfate. 4. The method of claim 2, wherein R1 is a methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl. 5. The method of claim 2, wherein the product comprises the formula: 6. A method of synthesizing an imaging agent precursor comprising: reacting a compound comprising formula (III): wherein: W is alkyl or heteroalkyl, optionally substituted; R1 is alkyl, optionally substituted; R2 is hydrogen or halide; each R3 can be the same or different and is alkyl optionally substituted with a leaving group or heteroalkyl optionally substituted with a leaving group; and n is 1, 2, 3, 4, or 5; provided at least one R3 is substituted with a leaving group; with a nucleophile, wherein the nucleophile replaces the leaving group to produce the imaging agent precursor. 7. A method of claim 6, wherein reacting the compound with the nucleophile occurs in the presence of a base. 8. A method of claim 7, wherein the base is a metal or metal salt. 9. A method of claim 6, wherein reacting the compound with the nucleophile occurs in the presence of a catalyst. 10. A method of claim 9, wherein the catalyst is a tetraalkylammonium iodide. 11. A method of claim 6, wherein: W is —O(CH2)—; R1 is t-butyl; R2 is chloride; and R3 is alkyl substituted with a leaving group. 12. A method of synthesizing an imaging agent, comprising: contacting an imaging agent precursor with a fluoride species and a bicarbonate salt under conditions that result in the fluoride species replacing the leaving group to produce an imaging agent comprising the fluoride species, wherein the molar ratio of bicarbonate salt to imaging agent precursor is less than about 1.5:1. 13. A method of manufacturing an imaging agent comprising the formula: wherein the method comprises, (a) contacting a tosylate precursor comprising the structure: with a fluoride species associated with an ammonium salt in the presence of a bicarbonate salt; (b) heating the mixture of (a); (c) cooling the heated mixture; (d) adding H2O to the cooled mixture; (e) purifying the mixture from the hydrated mixture of (d) using HPLC with an H2O/MeCN eluent; and (f) diluting the eluent with a solution of ascorbic acid or a salt thereof. 14. A method of synthesizing a fluorinated compound comprising 18F, comprising: reacting, in the presence of a bicarbonate salt, (i) a precursor of the fluorinated compound comprising an alkoxyalkyl group substituted with a halide or a sulfonate-containing group, with (ii) a salt comprising a fluoride species and weakly coordinating cation, wherein the fluoride species is enriched in 18F. 15. A method of synthesizing a product comprising an 18F-species, comprising reacting a compound comprising the formula: wherein R is -(lower alkyl)-sulfonate, R1 is an C1-C10 alkyl, and R2 is H or a halogen; with an 18F-containing species in the presence of a tetraalkylammonium bicarbonate salt to form the product comprising the 18F-species. 16. A method comprising: reacting a compound comprising formula (V): wherein: W is alkyl or heteroalkyl, optionally substituted; R1 is alkyl, optionally substituted; and R2 is hydrogen or halide, with a nucleophile or a radical species to produce a compound comprising formula (VI): 17. A method comprising: reacting precursor compounds comprising formulae: via an etherification reaction to form a first compound comprising the formula: exposing the first compound to a reducing agent to form a second compound comprising a benzylic alcohol; treating the second compound with phosphorus tribromide to form a third compound comprising a benzylic bromide; reacting the third compound with ethylene glycol to produce a fourth compound comprising the formula: reacting the fourth compound with a sulfonate-containing species to form a product comprising a sulfonate-containing precursor of an imaging agent. 18. A compound comprising formula: 19. A method of imaging a subject, comprising: subjecting a subject to stress; administering to the subject a dose of an imaging agent comprising the formula: in an amount less than about 20 mCi; and acquiring at least one first image of a portion of the subject. 20. A cassette for the preparation of an imaging agent comprising the formula: comprising: (i) a vessel containing an imaging agent precursor comprising the formula: and (ii) a conduit for adding a source of 18F.