Compounds for binding to the platelet specific glycoprotein IIB/IIIA and their use for imaging of thrombi

1. Compounds of Formula III:

wherein

R 3 is selected from the group consisting of H, F, CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN and NO 2 ;

R 7 is selected from the group consisting of Y, —O(CH 2 ) n —Y, —(OCH 2 CH 2 ) m —Y, Z, —OCH 2 —Z; —CH 2 —CH 2 —Z, —CH═CH—Z and —C≡C—Z;

X is selected from CH or N;

Y is selected from 18 F or F;

R 9 is hydrogen or (C 1 -C 6 ) alkyl;

R 10 is (C 1 -C 6 ) alkyl;

Z is a group

wherein * indicates the atom of connection of Z;

R 5 is selected from the group consisting of H, CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN and NO 2 ;

R 8 is selected from the group consisting of Y, —O(CH 2 ) n —Y and —(OCH 2 CH 2 ) m —Y;

n is 1-3;

and m is 2-3;

with the proviso that if R 7 has the meaning of Y, R 3 has the meaning of CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN or NO 2 and

with the proviso that if R 8 has the meaning of Y, R 5 has the meaning of CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN or NO 2 ;

including E and Z-isomers and diastereomers, mixtures thereof, and any pharmaceutically acceptable salt or complex thereof.

2. Compounds according to claim 1 ,

wherein

R 3 is H, F, CF 3 , CN or NO 2 ;

R 7 is Y, —O(CH 2 ) n —Y, —(OCH 2 CH 2 ) m —Y, Z, —OCH 2 —Z; —CH 2 —CH 2 —Z, —CH═CH—Z

or —C≡C—Z;

X is CH or N;

Y is 18 F or F;

Z is a group

wherein * indicates the atom of connection of Z;

R 5 is H, CF 3 , CN or NO 2 ;

R 8 is Y, —O(CH 2 ) n —Y or —(OCH 2 CH 2 ) m —Y;

n is 1-3;

and m is 2-3,

including E and Z-isomers and diastereomers, mixtures thereof, and any pharmaceutically acceptable salt or complex thereof.

3. Compounds according to claim 1 , wherein

R 3 is H;

R 7 is —O(CH 2 ) n —Y;

X is N;

Y is 18 F or F;

Z is a group

wherein * indicates the atom of connection of Z;

R 5 is H, CF 3 , CN or NO 2 ;

R 8 is Y, —O(CH 2 ) n —Y or —(OCH 2 CH 2 ) m —Y;

n is 1-3;

and m is 2-3,

including E and Z-isomers and diastereomers, mixtures thereof, and any pharmaceutically acceptable salt or complex thereof.

4. Compounds of Formula III according to claim 1 , selected from:

(3S)-3-[3-(2-fluoroethoxy)phenyl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}-carbonyl)amino]propanoic acid,

(3S)-3-[4-(2-fluoroethoxy)phenyl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-[5-(2-fluoroethoxy)pyridin-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}-carbonyl)amino]propanoic acid,

(3S)-3-(3-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}phenyl)-3-[({(3R)-1-[3-(piperidin-4-yl) propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-(5-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}pyridine-3-yl)-3-[({(3R)-1-[3-(piperidin-4-yl)-propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-{5-[3-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-[({(3R)-1-[3-(piperidin-4-yl) propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-{5-[4-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-{5-[2-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-[({(3R)-1-[3-(piperidin-4-yl) propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-[5-(3-cyano-4-fluorophenyl)pyridin-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl) propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-[5-(4-cyano-3-fluorophenyl)pyridin-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-[5-(4-fluoro-3-nitrophenyl)pyridin-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3R)-3-{5-[(3-cyano-4-fluorobenzyl)oxy]pyridin-3-yl}-3-[({(3S)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-{5-[(4-cyano-3-fluorobenzyl)oxy]pyridin-3-yl}-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-(4-cyano-3-fluorophenyl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-(5-{[4-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-(5-{[3-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-[5-fluoro-4′-(2-fluoroethoxy)biphenyl-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl) propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-(5-{2-[4-(2-fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-(5-{2-[4-(2-fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-(5-{2-[3-(2-fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(E/Z)(3S)-3-(5-{2-[3-(2-fluoroethoxy)phenyl]ethenyl}pyridin-3-yl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid, (3S)-3-[3-(2-[ 18 F]fluoroethoxy)phenyl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}-carbonyl)amino]propanoic acid,

(3S)-3-[4-(2-[ 18 F]fluoroethoxy)phenyl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-[5-(2-[ 18 F]fluoroethoxy)pyridin-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-{5-[4-(2-[ 18 F]fluoroethoxy)phenyl]pyridin-3-yl}-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-[5-(3-cyano-4-[ 18 F]fluorophenyl)pyridin-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-[5-(4-cyano-3-[ 18 F]fluorophenyl)pyridin-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-(5-{[4-(2-[ 18 F]fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-(5-{[3-(2-[ 18 F]fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-(5-{2-[4-(2-[ 18 F]fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-(5-{2-[3-(2-[ 18 F]fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid,

(3S)-3-(3-{2-[2-(2-[ 18 F]fluoroethoxy)ethoxy]ethoxy}phenyl)-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid.

5. Method for manufacturing of compounds of Formula III according to claim 1 :

wherein

R 3 is selected from the group consisting of H, F, CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN and NO 2 ; preferably R 3 is selected from the group consisting of H, F, CF 3 , CN, NO 2 ;

R 7 is selected from the group consisting of Y, —O(CH 2 ) n —Y, —(OCH 2 CH 2 ) m —Y, Z, —OCH 2 —Z; —CH 2 —CH 2 —Z, —CH═CH—Z and —C≡C—Z;

X is selected from CH or N;

Y is selected from 18 F or F;

R 9 is hydrogen or (C 1 -C 6 ) alkyl; preferably hydrogen or (C 1 -C 4 ) alkyl, more preferably hydrogen, methyl, ethyl or tert-butyl;

R 10 is (C 1 -C 6 ) alkyl; preferably (C 1 -C 4 ) alkyl, more preferably methyl, ethyl or tert-butyl;

Z is a group

wherein * indicates the atom of connection of Z;

R 5 is selected from the group consisting of H, CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN and

NO 2 ; preferably R 3 is selected from the group consisting of H, CF 3 , CN, NO 2 ;

R 8 is selected from the group consisting of Y, —O(CH 2 ) n —Y and —(OCH 2 CH 2 ) m —Y;

n is 1-3;

and m is 2-3;

with the proviso that if R 7 has the meaning of Y, R 3 has the meaning of CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN or NO 2 and

with the proviso that if R 8 has the meaning of Y, R 5 has the meaning of CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN or NO 2 ;

starting with compounds of Formula I,

wherein

R 1 is hydrogen or an amine-protecting group;

R 2 is hydrogen or a carboxyl-protecting group;

wherein at least one of R 1 and R 2 is not H;

R 3 is selected from the group consisting of H, F, CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN and NO 2 ; preferably R 3 is selected from the group consisting of H, F, CF 3 , CN, and NO 2 ;

R 4 is selected from the group consisting of OH, Halogen, —NO 2 , —N + (Me) 3 (W − ), —I + R 11 (W − )—O(CH 2 ) n -LG, —(OCH 2 CH 2 ) m -LG, Q, —OCH 2 -Q; —CH 2 —CH 2 -Q, —CH═CH-Q and —C≡C-Q;

preferably R 4 is selected from the group consisting of OH, Halogen, —N + (Me) 3 (W − ), —O(CH 2 ) n -LG, —(OCH 2 CH 2 ) m -LG, Q, —OCH 2 -Q; —CH 2 —CH 2 -Q, —CH═CH-Q and —C≡C-Q;

X is selected from CH or N;

LG is a leaving group;

R 9 is hydrogen or (C 1 -C 6 )alkyl; preferably hydrogen or (C 1 -C 4 ) alkyl, more preferably hydrogen, methyl, ethyl or tert-butyl;

R 10 is (C 1 -C 6 )alkyl; preferably (C 1 -C 4 ) alkyl, more preferably methyl, ethyl or tert-butyl;

R 11 is selected from the group consisting of phenyl, (4-methyl)phenyl, (4-methoxy)phenyl, 2-furanyl and 2-thienyl; preferably R 11 is selected from the group consisting of (4-methoxy)phenyl and 2-thienyl;

W − is selected from the group comprising CF 3 (S(O) 2 O − , iodide anion, bromide anion and CF 3 C(O)O − ; preferably W − is selected from the group CF 3 (S(O) 2 O − , bromide anion and CF 3 C(O)O − ;

Q is a group

wherein * indicates the atom of connection of Q;

R 5 is selected from the group consisting of H, CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN and NO 2 ; preferably R 5 is selected from the group consisting of H, CF 3 , CN, and NO 2

R 6 is selected from the group consisting of OH, Halogen, —NO 2 , —N + (Me) 3 (W − ), —I + R 11 (W − ), —O(CH 2 ) n -LG and —(OCH 2 CH 2 ) m -LG; preferably R 6 is selected from the group consisting of OH, Halogen, —N + (Me) 3 (W − ), —O(CH 2 ) n -LG and —(OCH 2 CH 2 ) m -LG;

n is 1-3;

and m is 2-3;

with the proviso that if R 4 has the meaning of Halogen, —NO 2 , —N + (Me) 3 (W − ) or —I + R 11 (W − ), R 3 has the meaning of CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN or NO 2 and

with the proviso that if R 6 has the meaning of Halogen, —NO 2 , —N + (Me) 3 (W − ) or —I + R 11 (W − ), R 5 has the meaning of CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN or NO 2 ;

and a fluorination reaction to obtain compounds of Formula II,

wherein

R 1 is hydrogen or an amine-protecting group;

R 2 is hydrogen or a carboxyl-protecting group;

wherein at least one of R 1 and R 2 is not hydrogen;

R 3 is selected from the group consisting of H, F, CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN and NO 2 ; preferably R 3 is selected from the group consisting of H, F, CF 3 , CN, NO 2 ;

R 7 is selected from the group consisting of Y, —O(CH 2 ) n —Y, —(OCH 2 CH 2 ) m —Y, Z, —OCH 2 —Z; —CH 2 —CH 2 —Z, —CH═CH—Z and —C≡C—Z;

X is selected from CH or N;

Y is selected from 18 F or F;

R 9 is hydrogen or (C 1 -C 6 )alkyl; preferably hydrogen or (C 1 -C 4 ) alkyl, more preferably hydrogen, methyl, ethyl or tert-butyl;

R 10 is (C 1 -C 6 )alkyl; preferably (C 1 -C 4 ) alkyl, more preferably methyl, ethyl or tert-butyl;

Z is a group

wherein * indicates the atom of connection of Z;

R 5 is selected from the group consisting of H, CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN and NO 2 ; preferably R 5 is selected from the group consisting of H, CF 3 , CN, NO 2 ;

R 8 is selected from the group consisting of Y, —O(CH 2 ) n —Y and —(OCH 2 CH 2 ) m —Y;

n is 1-3;

and m is 2-3;

with the proviso that if R 7 has the meaning Y, R 3 has the meaning of CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN or NO 2 and

with the proviso that if R 8 has the meaning Y, R 5 has the meaning of CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN or NO 2 ;

and cleavage of the protecting group(s)

or

reaction of compounds of Formula I with a 18 F or F reagent or 18 F or F building block and cleavage of protecting groups to obtain compounds of Formula III.

6. Method for manufacturing of compounds of Formula III according to claim 5 ,

wherein

R 3 is H, F, CF 3 , CN or NO 2 ;

R 7 is Y, —O(CH 2 ) n —Y, —(OCH 2 CH 2 ) m —Y, Z, —OCH 2 —Z; —CH 2 —CH 2 —Z, —CH═CH—Z or —C≡C—Z;

X is CH or N;

Y is 18 F or F;

Z is a group

wherein * indicates the atom of connection of Z;

R 5 is H, CF 3 , CN or NO 2 ;

R 8 is Y, —O(CH 2 ) n —Y or —(OCH 2 CH 2 ) m —Y;

n is 1-3;

and m is 2-3,

starting with compounds of Formula I

wherein

R 1 is hydrogen or an amine-protecting group;

R 2 is hydrogen or a carboxyl-protecting group;

wherein at least one of R 1 and R 2 is not H;

R 3 is H, F, CF 3 , CN and NO 2 ;

R 4 is OH, Halogen, —N + (Me) 3 (W − ), —O(CH 2 ) n -LG, —(OCH 2 CH 2 ) m -LG, Q, —OCH 2 -Q; —CH 2 —CH 2 -Q, —CH═CH-Q and —C≡C-Q;

X is CH or N;

LG is a leaving group;

W − is CF 3 (S(O) 2 O − , bromide anion and CF 3 C(O)O − ;

Q is a group

wherein * indicates the atom of connection of Q;

R 5 is H, CF 3 , CN and NO 2 ;

R 6 is OH, Halogen, —N + (Me) 3 (W − ), —O(CH 2 ) n -LG and —(OCH 2 CH 2 ) m -LG;

n is 1-3;

and m is 2-3;

with the proviso that if R 4 has the meaning of Halogen or —N + (Me) 3 (W − ), R 3 has the meaning of CF 3 , CN or NO 2 and

with the proviso that if R 6 has the meaning of Halogen or —N + (Me) 3 (W − ), R 5 has the meaning of CF 3 , CN or NO 2 ;

and a fluorination reaction to obtain compounds of Formula II,

wherein

R 1 is hydrogen or an amine-protecting group;

R 2 is hydrogen or a carboxyl-protecting group;

wherein at least one of R 1 and R 2 is not hydrogen;

R 3 is H, F, CF 3 , CN and NO 2 ;

R 7 is Y, —O(CH 2 ) n —Y, —(OCH 2 CH 2 ) m —Y, Z, —OCH 2 —Z; —CH 2 —CH 2 —Z, —CH═CH—Z or —C≡C—Z;

X is CH or N;

Y is 18 F or F;

Z is a group

wherein * indicates the atom of connection of Z;

R 5 is H, CF 3 , CN and NO 2 ;

R 8 is Y, —O(CH 2 ) n —Y or —(OCH 2 CH 2 ) m —Y;

n is 1-3;

and m is 2-3;

with the proviso that if R 7 has the meaning of Y, R 3 has the meaning of CF 3 , CN or NO 2 and with the proviso that if R 8 has the meaning of Y, R 5 has the meaning of CF 3 , CN or NO 2 ;

and cleavage of the protecting group(s)

or

reaction of compounds of Formula I with a 18 F or F reagent or 18 F or F building block and cleavage of protecting groups to obtain compounds of Formula III.

7. A method for diagnostic imaging which comprises administering a compound of Formula III of claim 1 .

8. A method according to claim 7 , wherein the method is for imaging thrombi.

9. A method for the manufacture of a diagnostic agent, which comprises formulating a compound of Formula III of claim 1 into a form suitable for administration to a patient in order to perform diagnostic imaging.

10. A compound of Formula III according to claim 1 , which is:

(3S)-3-[5-(2-[ 18 F]fluoroethoxy)pyridin-3-yl]-3-[({(3R)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid, having the following structure

11. Compounds of Formula II:

wherein

R 1 is hydrogen or an amine-protecting group;

R 2 is hydrogen or a carboxyl-protecting group;

wherein at least one of R 1 and R 2 is not hydrogen;

R 3 is selected from the group consisting of H, F, CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN and NO 2 ; preferably R 3 is selected from the group consisting of H, F, CF 3 , CN, NO 2 ;

R 7 is selected from the group consisting of Y, —O(CH 2 ) n —Y, —(OCH 2 CH 2 ) m —Y, Z, —OCH 2 —Z; —CH 2 —CH 2 —Z, —CH═CH—Z and —C≡C—Z;

X is selected from CH or N;

Y is selected from 18 F or F;

R 9 is hydrogen or (C 1 -C 6 )alkyl; preferably hydrogen or (C 1 -C 4 ) alkyl, more preferably hydrogen, methyl, ethyl or tert-butyl;

R 10 is (C 1 -C 6 )alkyl; preferably (C 1 -C 4 ) alkyl, more preferably methyl, ethyl or tert-butyl;

Z is a group

wherein * indicates the atom of connection of Z;

R 5 is selected from the group consisting of H, CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN and NO 2 ; preferably R 5 is selected from the group consisting of H, CF 3 , CN, NO 2 ;

R 8 is selected from the group consisting of Y, —O(CH 2 ) n —Y and —(OCH 2 CH 2 ) m —Y;

n is 1-3;

and m is 2-3;

with the proviso that if R 7 has the meaning Y, R 3 has the meaning of CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN or NO 2 and

with the proviso that if R 8 has the meaning Y, R 5 has the meaning of CF 3 , COR 9 , COOR 10 , SOR 10 , SO 2 R 10 , CN or NO 2 ;

including E and Z-isomers and diastereomers, mixtures thereof, and any pharmaceutically acceptable salt or complex thereof.

12. Compounds according to claim 11 ,

wherein

R 1 is hydrogen or an amine-protecting group;

R 2 is hydrogen or a carboxyl-protecting group;

wherein at least one of R 1 and R 2 is not hydrogen;

R 3 is H, F, CF 3 , CN and NO 2 ;

R 7 is Y, —O(CH 2 ) n —Y, —(OCH 2 CH 2 ) m —Y, Z, —OCH 2 —Z; —CH 2 —CH 2 —Z, —CH═CH—Z or —C≡C—Z;

X is CH or N;

Y is 18 F or F;

Z is a group

wherein * indicates the atom of connection of Z;

R 5 is H, CF 3 , CN and NO 2 ;

R 8 is Y, —O(CH 2 ) n —Y or —(OCH 2 CH 2 ) m —Y;

n is 1-3;

and m is 2-3;

with the proviso that if R 7 has the meaning of Y, R 3 has the meaning of CF 3 , CN or NO 2 and

with the proviso that if R 8 has the meaning of Y, R 5 has the meaning of CF 3 , CN or NO 2 ;

including E and Z-isomers and diastereomers and mixtures thereof.

13. Compounds according to claim 11 ,

wherein

R 1 is hydrogen or an amine-protecting group selected from the group comprising tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz) and 9-fluorenylmethyloxycarbonyl (FMOC);

R 2 is hydrogen or a carboxyl-protecting group selected from the group comprising methyl, ethyl, propyl, tert-butyl, benzyl and p-methoxybenzyl;

wherein at least one of R 1 and R 2 is not hydrogen;

R 3 is H, F, CF 3 , CN and NO 2 ;

R 7 is Y, —O(CH 2 ) n —Y, —(OCH 2 CH 2 ) m —Y, Z, —OCH 2 —Z; —CH 2 —CH 2 —Z, —CH═CH—Z or —C≡C—Z;

X is N;

Y is 18 F or F;

Z is a group

wherein * indicates the atom of connection of Z;

R 5 is H, CF 3 , CN and NO 2 ;

R 8 is Y, —O(CH 2 ) n —Y or —(OCH 2 CH 2 ) m —Y;

n is 1-3;

and m is 2-3;

with the proviso that if R 7 has the meaning of Y, R 3 has the meaning of CF 3 , CN or NO 2 and

with the proviso that if R 8 has the meaning of Y, R 5 has the meaning of CF 3 , CN or NO 2 ;

including E and Z-isomers and diastereomers and mixtures thereof.

14. Compounds according to claim 11 ,

wherein

R 1 is tert-butyloxycarbonyl (BOC);

R 2 is methyl or tert-butyl;

wherein at least one of R 1 and R 2 is not hydrogen;

R 3 is H;

R 7 is —O(CH 2 ) n —Y;

X is N;

Y is 18 F or F;

Z is a group

wherein * indicates the atom of connection of Z;

R 5 is H, CF 3 , CN and NO 2 ;

R 8 is Y, —O(CH 2 ) n —Y or —(OCH 2 CH 2 ) m —Y;

n is 1-3;

and m is 2-3;

with the proviso that if R 7 has the meaning of Y, R 3 has the meaning of CF 3 , CN or NO 2 and

with the proviso that if R 8 has the meaning of Y, R 5 has the meaning of CF 3 , CN or NO 2 ;

including E and Z-isomers and diastereomers and mixtures thereof.

15. Compounds of Formula II according to claim 11 , selected from:

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-[3-(2-fluoroethoxy)phenyl]propanoic acid,

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-[4-(2-fluoroethoxy)phenyl]propanoic acid,

tert-butyl 4-{3-[(3R)-3-({(1S)-3-tert-butoxy-1-[5-(2-fluoroethoxy)pyridin-3-yl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(3-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}phenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}pyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl 4-{3-[(3R)-3-{[1-{5-[3-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-{5-[3-(2-fluoroethoxy)phenyl]pyridin-3-yl}propanoic acid,

tert-butyl 4-(3-{(3R)-3-[(1-{5-[4-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate,

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-{5-[4-(2-fluoroethoxy)phenyl]pyridin-3-yl}propanoic acid,

tert-butyl 4-(3-{(3R)-3-[(1-{5-[2-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate,

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]-carbonyl}amino)-3-{5-[2-(2-fluoroethoxy)phenyl]pyridin-3-yl}propanoic acid,

tert-butyl 4-{3-[(3R)-3-({1-[5-(3-cyano-4-fluorophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-[5-(3-cyano-4-fluorophenyl)pyridin-3-yl]propanoic acid,

tert-butyl 4-{3-[(3R)-3-({1-[5-(4-cyano-3-fluorophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-[5-(4-cyano-3-fluorophenyl)pyridin-3-yl]propanoic acid,

tert-butyl 4-{3-[(3R)-3-({1-[5-(4-fluoro-3-nitrophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-[5-(4-fluoro-3-nitrophenyl)pyridin-3-yl]propanoic acid,

tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{5-[(3-cyano-4-fluorobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{5-[(4-cyano-3-fluorobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{[4-(2-fluoroethoxy)phenyl]ethynyl}-pyridine-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{[3-(2-fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl 4-{3-[(3R)-3-({1-[5-fluoro-4′-(2-fluoroethoxy)biphenyl-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-[5-fluoro-4′-(2-fluoroethoxy)biphenyl-3-yl]propanoic acid,

tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-({[4-(2-fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-({[3-(2-fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

(E/Z) tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-({[3-(2-fluoroethoxy)phenyl]ethenyl}pyridin-3-yl)-3-oxopropyl]-carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{3-[2-[ 18 F]fluoroethoxy]phenyl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate

(3S)-3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]-carbonyl}amino)-3-{3-[2-[ 18 F]fluoroethoxy]phenyl}propanoic acid,

tert-butyl 4-{3-[(3R)-3-({1-[4-(2-[ 18 F]fluoroethoxy)phenyl]-3-methoxy-3-oxopropyl}-carbamoyl)-piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-{4-[2-[ 18 F]fluoroethoxy]phenyl}propanoic acid,

tert-butyl 4-{3-[(3R)-3-({(1S)-3-tert-butoxy-1-[5-(2-[ 18 F]fluoroethoxy)pyridin-3-yl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl 4-{3-[(3R)-3-({(1S)-1-[5-(2-[ 18 F]fluoroethoxy)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

(3S)-3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-{5-[2-[ 18 F]fluoroethoxy]pyridin-3-yl}propanoic acid,

tert-butyl 4-(3-{(3R)-3-[(1-{5-[2-[ 18 F]fluoroethoxy]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate,

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]-carbonyl}amino)-3-{5-[2-[ 18 F]fluoroethoxy]pyridin-3-yl}propanoic acid,

tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(5-{4-[2-[ 18 F]fluoroethoxy]phenyl}pyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

(3S)-3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]-carbonyl}amino)-3-(5-{-4-[2-[ 18 F]fluoroethoxy]phenyl}pyridin-3-yl)propanoic acid,

tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{4-[2-[ 18 F]fluoroethoxy]phenyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl 4-(3-{(3R)-3-[(1-{5-[3-cyano-4-[ 18 F]fluorophenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate,

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-[5-(3-cyano-4-[ 18 F]fluorophenyl)pyridin-3-yl]propanoic acid,

tert-butyl 4-(3-{(3R)-3-[(1-{5-[4-cyano-3-[ 18 F]fluorophenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl)carbamoyl]piperidin-1-yl}-3-oxopropyl)piperidine-1-carboxylate,

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-{5-[4-cyano-3-[ 18 F]fluorophenyl]pyridin-3-yl}propanoic acid,

tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{[4-(2-[ 18 F]fluoroethoxy)phenyl]ethynyl}-pyridine-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-{[3-(2-[ 18 F]fluoroethoxy)phenyl]ethynyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-({[4-(2-[ 18 F]fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-({[3-(2-[ 18 F]fluoroethoxy)phenyl]ethyl}pyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate,

tert-butyl 4-{3-[(3R)-3-({1-[3-(2-{2-[2-[ 18 F]fluoroethoxy]ethoxy}ethoxy)phenyl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate, and

3-({[(3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidin-3-yl]carbonyl}amino)-3-[3-(2-{2-[2-[ 18 F]fluoroethoxy]ethoxy}ethoxy)phenyl]propanoic acid.