Compositions, methods, and systems for the synthesis and use of imaging agents

Patent metadata

Field	Value
Publication number	US-9550000-B2
Application number	US-201214343627-A
Country	US
Kind code	B2
Filing date	Sep 7, 2012
Priority date	Sep 9, 2011
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

The present invention relates to systems, compositions, and methods for the synthesis and use of imaging agents, or precursors thereof. An imaging agent precursor may be converted to an imaging agent using the methods described herein. In some cases, the imaging agent is enriched in 18 F. In some cases, an imaging agent may be used to image an area of interest in a subject, including, but not limited to, the heart, cardiovascular system, cardiac vessels, brain, and other organs. In some embodiments, methods and compositions for assessing perfusion and innervation mismatch in a portion of a subject are provided.

First claim

What is claimed:

1. A method of determining perfusion and innervation mismatch in a portion of a human subject, comprising:
administering to the subject a first imaging agent and acquiring at least one first image of a portion of the subject, wherein the first imaging agent is employed to image perfusion;
administering to the subject a second imaging agent and acquiring at least one second image of the portion of the subject, wherein the second imaging agent is employed to image innervation; and
determining regional mismatch of innervation and perfusion areas in the portion of the subject based at least in part on the at least one first image and the at least one second image, wherein the first imaging agent has the structure:

wherein
J is selected from the group consisting of N(R 28 ), S, O, C(═O), C(═O)O, NHCH 2 CH 2 O, a bond, and C(═O)N(R 27 );
when present, K is selected from the group consisting of hydrogen, alkoxyalkyl optionally substituted with an imaging moiety, alkyloxy optionally substituted with an imaging moiety, aryl optionally substituted with an imaging moiety, C 1 -C 6 alkyl optionally substituted with an imaging moiety, heteroaryl optionally substituted with an imaging moiety, and an imaging moiety;
when present, L is selected from the group consisting of hydrogen, alkoxyalkyl optionally substituted with an imaging moiety, alkyloxy optionally substituted with an imaging moiety, aryl optionally substituted with an imaging moiety, C 1 -C 6 alkyl optionally substituted with an imaging moiety, heteroaryl optionally substituted with an imaging moiety, and an imaging moiety;
M is selected from the group consisting of hydrogen, alkoxyalkyl optionally substituted with an imaging moiety, alkyloxy optionally substituted with an imaging moiety, aryl optionally substituted with an imaging moiety, C 1 -C 6 alkyl optionally substituted with an imaging moiety, heteroaryl optionally substituted with an imaging moiety, and an imaging moiety; or
L and M, together with the atom to which they are attached, may form a three- or four-membered carbocyclic ring;
Q is halo or haloalkyl;
n is 0, 1, 2, or 3;
R 21 , R 22 , R 27 , and R 28 are independently selected from hydrogen, C 1 -C 6 alkyl optionally substituted with an imaging moiety, and an imaging moiety;
R 23 , R 24 , R 25 , and R 26 are independently selected from hydrogen, halogen, hydroxyl, alkyloxy, C 1 -C 6 alkyl optionally substituted with an imaging moiety, and an imaging moiety; R 29 is C 1 -C 6 alkyl optionally substituted with an imaging moiety; and Y
is selected from the group consisting of a bond, carbon, and oxygen; provided that when Y is a bond, K and L are absent, and M is selected from the group consisting of aryl optionally substituted with an imaging moiety and heteroaryl optionally substituted with an imaging moiety; and provided that when Y is oxygen, K and L are absent, and M is selected from hydrogen, alkoxyalkyl optionally substituted with an imaging moiety, aryl optionally substituted with an imaging moiety, C 1 -C 6 alkyl optionally substituted with an imaging moiety, and heteroaryl optionally substituted with an imaging moiety;
provided that at least one imaging moiety is present,
or a salt thereof.

2. The method of claim 1 , wherein the first imaging agent has the structure:

or a pharmaceutically acceptable salt thereof.

3. The method of claim 2 , wherein the second imaging agent has the structure:

or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein the second imaging agent is of the formula:
R 0 —Ar-L-R 1

wherein
Ar is substituted or unsubstituted, monocyclic or bicyclic aryl or substituted or unsubstituted, monocyclic or bicyclic heteroaryl;
L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene; substituted or unsubstituted, cyclic or acyclic alkenylene; substituted or unsubstituted, cyclic or acyclic alkynylene; or substituted or unsubstituted, cyclic or acyclic heteroaliphatic;
R 1 is a substituted or unsubstituted nitrogen-containing moiety; and

R 0 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A1 , —N(R A2 ) 2 , —SR A1 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)SR A1 , —C(═O)N(R A2 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A2 ) 2 , —NR A2 C(═O)R A2 , —NR A2 C(═O)OR A1 , —NR A2 C(═O)SR A1 , —NR A2 C(═O)N(R A2 ) 2 , —SC(═O)R A1 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A2 ) 2 , —C(═NR A2 )R A1 , —C(═NR)OR A1 , —C(═NR A2 )SR A1 , —C(═NR A2 )N(R A2 ) 2 , —OC(═NR A2 )R A1 , —OC(═NR A2 )OR A1 , —OC(═NR A2 )SR A1 , —OC(═NR A2 )N(R A2 ) 2 , —NR A2 C(═NR A2 )R A2 , —NR A2 C(═NR)OR A1 , —NR A2 C(═NR A2 )SR A1 , —NR A2 C(═NR A2 )N(R A2 ) 2 , —SC(═NR A2 )R A1 , —SC(═NR A1 )OR A1 , —SC(═NR A2 )SR A1 , —SC(═NR A2 )N(R A2 ) 2 , —C(═S)R A1 , —C(═S)OR A1 , —C(═S)SR A1 , —C(═S)N(R A2 ) 2 , —OC(═S)R A1 , —OC(═S)OR A1 , —OC(═S)SR A1 , —OC(═S)N(R A2 ) 2 , —NR A2 C(═S)R A2 , —NR A2 C(═S)OR A1 , —NR A2 C(═S)SR A1 , —NR A2 C(═S)N(R A2 ) 2 , —SC(═S)R A1 , —SC(═S)OR A1 , —SC(═S)SR A1 , —SC(═S)N(R A2 ) 2 , —S(═O)R A1 , —SO 2 R A1 , —NR A2 SO 2 R A1 , —SO 2 N(R A2 ) 2 , —CN, —SCN, or —NO 2 ;
each occurrence of R A1 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and each occurrence of R A2 is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, or two R A2 groups are joined to form an optionally substituted heterocyclic ring; and
R 0 or R 1 is substituted with an imaging moiety selected from the group consisting of 18 F, 76 Br, 124 I, and 131 I, or is associated with an imaging moiety selected from the group consisting of 64 Cu, 89 Zr, 99m Tc, and 111 In through a chelator, or is an imaging moiety selected from the group consisting of 18 F, 76 Br, 124 I, and 131 I;
or a salt thereof.

5. The method of claim 1 , wherein the second imaging agent is of the formula of the formula:
R 0 —Ar-L-R 1

wherein
Ar is substituted or unsubstituted, monocyclic or bicyclic aryl or substituted or unsubstituted, monocyclic or bicyclic heteroaryl;
L is a bond; substituted or unsubstituted, cyclic or acyclic alkylene; substituted or unsubstituted, cyclic or acyclic alkenylene; substituted or unsubstituted, cyclic or acyclic alkynylene; or substituted or unsubstituted, cyclic or acyclic heteroaliphatic;
R 1 is a substituted or unsubstituted nitrogen-containing moiety; and

R 0 is halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A1 , —N(R A2 ) 2 , —SR A1 , —C(═O)R A1 , —C(═O)OR A1 , —C(═O)SR A1 , —C(═O)N(R A2 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A2 ) 2 , —NR A2 C(═O)R A2 , —NR A2 C(═O)OR A1 , —NR A2 C(═O)SR A1 , —NR A2 C(═O)N(R A2 ) 2 , —SC(═O)R A1 , —SC(

Assignees

• Robinson Simon P
• Yu Ming
• Lantheus Medical Imaging Inc

Inventors

• Robinson Simon P
• Yu Ming

Classifications

• C07C217/70

  linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring · CPC title

• C07C279/14

  being further substituted by carboxyl groups · CPC title

• C07D239/42

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• C07C257/14 Primary

  having carbon atoms of amidino groups bound to acyclic carbon atoms · CPC title

• C07C279/08

  being further substituted by singly-bound oxygen atoms · CPC title