Zinc sensors for in vivo imaging of beta-cell function by MRI
In some aspects, the present disclosure provides gadolinium based sensors which may be used to image zinc ions in vivo. In some embodiments, the compounds show appropriate reactivity with zinc ions while maintaining high relaxivity to achieve improved background relative to other sensors.
1. A compound of the formula:
wherein:
A 1 , A 2 , A 3 , and A 4 are each independently C1-C4 alkanediyl or substituted C1-C4 alkanediyl; and
R 2 , R 3 , and R 4 are each independently hydroxy, amino, C1-C12 alkylamino, substituted C1-C12 alkylamino, C1-C12 dialkylamino, or substituted C1-C12 dialkylamino;
R 1 is
wherein:
As and A6 are each independently C1-C4 alkanediyl or substituted C1-C4 alkanediyl; and
X 1 and X 2 are each independently C1-C12 heteroaryl or substituted C1-C12 heteroaryl;
provided that at least one of A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 is not —CH 2 —;
or a metal complex, a deprotonated form, or a salt thereof.
2. The compound of claim 1 further defined as:
wherein:
A 1 and A 4 are each independently C1-C4 alkanediyl or substituted C1-C4 alkanediyl; and
R 4 is hydroxy, amino, C1-C12 alkylamino, substituted C1-C12 alkylamino, C1-C12 dialkylamino, or substituted C1-C12 dialkylamino;
R 1 is
wherein:
A 5 and A 6 are each independently C1-C4 alkanediyl or substituted C1-C4 alkanediyl; and
X 1 and X 2 are each independently C1-C12 heteroaryl or substituted C1-C12 heteroaryl;
provided that at least one of A 1 , A 4 , A 5 , and A 6 is not —CH 2 —;
or a metal complex, a deprotonated form, or a salt thereof.
3. The compound of claim 2 further defined as:
wherein:
m and n are each independently 1 or 2; and
R 1 is
wherein:
x and y is 1 or 2; and
X 1 and X 2 are each independently C1-C12 heteroaryl or substituted C1-C12 heteroaryl;
provided that at least one of m, n, x, and y is not 1;
or a metal complex, a deprotonated form, or a salt thereof.
4. The compound of claim 1 , wherein A 1 is C1-C3 alkanediyl.
5. The compound of claim 1 , wherein A 2 , A 3 , A 5 , and A 6 are C1-C3 alkanediyl.
6. The compound of claim 1 , wherein A 4 is C1-C3 alkanediyl.
7. The compound of claim 1 , wherein R 2 , R 3 , and R 4 are hydroxy.
8. The compound of claim 1 , wherein X 1 and X 2 are C1-C12 heteroaryl.
9. The compound of claim 1 , wherein the compound is further defined as:
or a deprotonated form or salt thereof.
10. The compound of claim 1 , wherein the compound is further defined as a metal complex of the formula:
wherein:
A 1 , A 2 , A 3 , and A 4 are each independently C1-C4 alkanediyl or substituted C1-C4 alkanediyl; and
R 2 , R 3 , and R 4 are each independently hydroxy, amino, C1-C12 alkylamino, substituted C1-C12 alkylamino, C1-C12 dialkylamino, or substituted C1-C12 dialkylamino;
R 1 is
wherein:
A 5 and A 6 are each independently C1-C4 alkanediyl or substituted C1-C4 alkanediyl; and
X 1 and X 2 are each independently C1-C12 heteroaryl or substituted C1-C12 heteroaryl;
provided that at least one of A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 is not —CH 2 —;
or a deprotonated form or a salt thereof.
11. The compound of claim 10 , wherein the metal complex is further defined by the formula:
wherein:
A 1 and A 4 are each independently C1-C4 alkanediyl or substituted C1-C4 alkanediyl; and
R 4 is hydroxy, amino, C1-C12 alkylamino, substituted C1-C12 alkylamino, C1-C12 dialkylamino, or substituted C1-C12 dialkylamino;
R 1 is
wherein:
As and A6 are each independently C1-C4 alkanediyl or substituted C1-C4 alkanediyl; and
X 1 and X 2 are each independently C1-C12 heteroaryl or substituted C1-C12 heteroaryl;
provided that at least one of A1, A4, As, and A6 is not —CH 2 —;
or a deprotonated form or a salt thereof.
12. The compound of claim 11 , wherein the metal complex is further defined by the formula:
wherein:
m and n are each independently 1, 2, 3, or 4; and
R 1 is
wherein:
x and y is 1, 2, 3, or 4; and
X 1 and X 2 are each independently C1-C12 heteroaryl or substituted C1-C12 heteroaryl;
provided that at least one of m, n, x, and y is 1;
or a deprotonated form, or a salt thereof.
13. The compound of claim 1 , wherein the compound is further defined as:
or a deprotonated form or salt thereof.
14. A pharmaceutical composition comprising:
(A) a compound of claim 1 ; and
(B) an excipient.
15. A method of imaging the pancreas in vivo in a patient to determine the onset of (3-cell degeneration comprising the steps of:
(A) administering to the patient a compound of claim 1 ;
(B) obtaining an imaging scan of the patient; and
(C) determining the presence of Zn 2+ ions by analyzing the imaging scan of the patient to determine the presence of Zn 2+ ions.
16. A method of imaging the prostate in vivo in a patient to determine the presence of a prostate tumor comprising the steps of:
(A) administering to the patient a compound of claim 1 ;
(B) obtaining an imaging scan of the patient; and
(C) determining the presence of Zn 2+ ions by analyzing the imaging scan of the patient to determine the presence of Zn 2+ ions.
17. A method of imaging the pancreas in vivo in a patient to determine the secretion of insulin comprising the steps of:
(A) administering to the patient a compound of claim 1 ;
(B) obtaining an imaging scan of the patient; and
(C) determining the presence of Zn 2+ ions by analyzing the imaging scan of the patient to determine the presence of Zn 2+ ions.