Ligands for imaging cardiac innervation

Patent metadata

Field	Value
Publication number	US-10010631-B2
Application number	US-201313916205-A
Country	US
Kind code	B2
Filing date	Jun 12, 2013
Priority date	Dec 26, 2006
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

Abstract

Novel compounds that find use as imaging agents within nuclear medicine applications (PET imaging) for imaging of cardiac innervation are disclosed. These PET based radiotracers may exhibit increased stability, decreased NE release (thereby reducing side effects), improved quantitative data, and/or high affinity for VMAT over prior radiotracers. Methods of using the compounds to image cardiac innervation are also provided. In some instances the compounds are developed by derivatizing certain compounds with 18F in a variety of positions: aryl, alkyl, a keto, benzylic, beta-alkylethers, gamma-propylalkylethers and beta-proplylalkylethers. Alternatively or additionally, a methyl group a is added to the amine, and/or the catechol functionality is either eliminated or masked as a way of making these compounds more stable.

First claim

What is claimed is:

1. A compound of the structure:

or a salt thereof,
wherein n is 0;
A and R 2 are absent;
X, W, R and R 3 are hydrogen;
R 1 is NHC(═NH)NH 2 ;
Y is H, F, Cl, or Br; and
Z is OR 4 and R 4 is alkyl substituted with 18 F.

2. A method of imaging cardiac innervation comprising the steps of:
administering an effective amount of the compound of claim 1 or a salt thereof to a patient;
detecting radiation emitted by said compound; and
forming an image therefrom.

3. The compound of claim 1 , wherein the compound is a salt.

4. The compound of claim 1 , wherein the compound is a salt of a compound selected from the group consisting of:

5. A composition for imaging cardiac innervation comprising the compound of claim 4 , and optionally one or more excipients.

6. A method of imaging cardiac innervation comprising the steps of:
administering an effective amount of the compound of claim 4 to a patient;
detecting radiation emitted by said compound; and
forming an image therefrom.

7. The compound of claim 1 , wherein the compound is a salt of the compound:

8. The compound of claim 7 , wherein the salt has the structure N-[3-bromo-4(3-[18F]fluoropropoxy)-benzyl]-guanidine hydrochloride.

9. A composition for imaging cardiac innervation comprising the compound of claim 7 , and optionally one or more excipients.

10. A method of imaging cardiac innervation comprising the steps of:
administering an effective amount of the compound of claim 7 to a patient;
detecting radiation emitted by said compound; and
forming an image therefrom.

11. A composition for imaging cardiac innervation comprising the compound of claim 1 , and optionally one or more excipients.

12. A compound of the structure:

or a salt thereof,
wherein n is 1;
A is absent;
R 2 is hydrogen or OR 4 , wherein R 4 is H or alkyl;
X, W, R and R 3 are hydrogen;
R 1 is NHC(═NH)NH 2 ;
Y is H, F, Cl, or Br; and
Z is OR 4 , wherein R 4 is alkyl substituted with 18 F.

13. A compound of the structure:

or a salt thereof,
wherein n is 0 or 1;
A is absent;
R 2 , when present, is hydrogen or OR 4 , wherein R 4 is H or alkyl;
X, W, R and R 3 are hydrogen;
R 1 is NHC(═NH)NH 2 ;
Z is H, F, Cl, or Br; and
Y is OR 4 , wherein R 4 is alkyl substituted with 18 F.

14. A compound of the structure:

or a salt thereof,
wherein n is 0 or 1;
R is NR 4 C(═NR 5 )NHR 6 ;
R 1 is selected from the group consisting of H and alkyl (C 1 -C 4 );
when present, R 2 is H or OR 4
R 3 is H;
R 4 , R 5 , and R 6 are independently selected from the group consisting of H and alkyl (C 1 -C 8 ), wherein one or more R 4 -R 6 may be substituted with an imaging moiety;
A is absent;
W and X are hydrogen; and
Y and Z are independently selected from the group consisting of H, OR 4 , F, Cl, Br, and I,
wherein Y or Z is OR 4 and R 4 is alkyl substituted with 18 F.

15. The compound of claim 14 , wherein the compound has the structure:

or a salt thereof.

16. A method of imaging cardiac innervation comprising the steps of:
administering an effective amount of the compound of claim 12 or a salt thereof to a patient;
detecting radiation emitted by said compound; and
forming an image therefrom.

17. A method of imaging cardiac innervation comprising the steps of:
administering an effective amount of the compound of claim 13 or a salt thereof to a patient;
detecting radiation emitted by said compound; and
forming an image therefrom.

18. A method of imaging cardiac innervation comprising the steps of:
administering an effective amount of the compound of claim 15 or a salt thereof to a patient;
detecting radiation emitted by said compound; and
forming an image therefrom.

19. A method of imaging cardiac innervation comprising the steps of:
administering an effective amount of the compound of claim 14 or a salt thereof to a patient;
detecting radiation emitted by said compound; and
forming an image therefrom.

20. The compound of claim 13 , wherein n is 0.

21. The compound of claim 14 , wherein n is 0.

22. The compound of claim 13 , wherein n is 1.

23. The compound of claim 14 , wherein n is 1.

Assignees

• Lantheus Medical Imaging Inc

Inventors

• Purohit Ajay
• Harris Thomas D
• Radeke Heike S
• Robinson Simon P
• Yu Ming
• Casebier David S
• Azure Michael T

Classifications

• A61K51/0459

  having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine · CPC title

• C07B59/001

  Acyclic or carbocyclic compounds · CPC title

• C07D233/54

  having two double bonds between ring members or between ring members and non-ring members · CPC title

• 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

• C07C279/06

  being further substituted by halogen atoms, or by nitro or nitroso groups · CPC title