RADIOISOTOPE-LABELED LYSINE AND ORNITHINE DERIVATIVES, THEIR USE AND PROCESSES FOR THEIR PREPARATION

1 . A compound of formula I

wherein

R 1 , R 2 and R 3 are selected independently and individually from the group comprising

a) hydrogen,

b) R 7 —C 1 -C 10 alkoxy,

c) R 7 —C 1 -C 10 alkyl,

d) R 7 —C 2 -C 10 alkenyl,

e) R 7 —C 2 -C 10 alkinyl,

f) (R 7 -aryl)-C 0 -C 10 alkyl,

g) (R 7 -heteroaryl)-C 0 -C 10 alkyl,

h) ((R 7 —(C 1 -C 6 )alkoxy)aryl)(C 0 -C 10 )alkyl),

i) R 7 ,

j) hydroxyl,

k) C 6 -C 10 aralkyl,

l) C 1 -C 10 alkyl and

m) C 1 -C 10 alkoxy;

R 4 is selected from the group comprising

a) NH 2 and

b) R 14 ;

R 5 is selected from the group comprising

a) hydrogen,

b) Z and

c) R 13 ;

R 6 is selected from the group comprising

a) NH 2 and

b) R 14 ;

R 7 is selected from the group comprising

a) [ 19 F]fluoro,

b) Chelator free radionuclide,

c) R 15 and

d) R 10 ;

R 10 is selected from the group comprising R 20 and R 30 ;

R 15 is a leaving group;

R 14 is selected from the group comprising

a) N(H)(R 9 ),

b) N(R 9 ) 2 .

c) N═C(R 11 )(R 12 )

d) 1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl (phthalimido) and

e) azido group;

R 13 is a carboxylic acid protecting group;

R 20 is selected from the group comprising

a) iodo,

b) —Sn((C 1 -C 6 )alkyl) 3 ,

c)—B(OR 60 )(OR 61 ) wherein B means boron and

d)—NMe 2 ;

R 30 is hydroxyl;

Z is a metal ion equivalent;

R 9 is an amino-protecting group;

R 11 and R 12 are independently and individually selected from the group comprising

a) C 1 -C 5 alkyl,

b) substituted or unsubstituted aryl,

c) substituted or unsubstituted aralkyl and

d) substituted or unsubstituted heteroaryl;

R 60 and R 61 are independently and individually selected from the group comprising hydrogen, (C 1 -C 6 )alkyl and cycloalkyl, whereas R 60 and R 61 can be linked to each other by a single bond or a “methylene bridge”;

k is an integer from 1 to 4;

including all isomeric forms of said compound, including but not limited to enantiomers and diastereoisomers as well as racemic mixtures;

and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof.

2 . The compound according to claim 1 wherein

R 1 , R 2 and R 3 are selected individually and independently from the group comprising

a) hydrogen,

b) R 7 —C 1 -C 6 Alkyl,

c) R 7 and

d) C 1 -C 5 Alkyl.

with the proviso that compounds of Formula I contain exactly one R 7 ;

3 . The compound according to claim 2 wherein

R 7 is a chelator free radionuclide.

4 . The compound according to claim 3 wherein the chelator free radionuclide is Bromo-77 [ 77 Br], Bromo-76 [ 76 Br], Oxygen-15 [ 15 O], Nitrogen-13 [ 13 N], Carbon-11 [ 11 C], iodine-123 [ 123 ]iodo, iodine-124 [ 124 iodo], iodine-125 [ 125 iodo], iodine-127 [ 127 iodo], iodine-131 [ 131 iodo] or Fluorine-18 [ 18 F], preferably Fluorine-18 [ 18 F].

5 . The compound according to claim 1 wherein Z is selected from the group comprising Na + , K + , Ca 2+ and Mg 2+ .

6 . The compound according to claim 1 wherein independently from each other

k is an integer 1 or 2, and

n is an integer 1 or 2,

7 . The compound according to claim 1 selected from

(4R)—N 5 -[(benzyloxy)carbonyl]-N 2 -(tert-butoxycarbonyl)-4-hydroxy-L-ornithinate (26)

(4R)—N 5 -[(benzyloxy)carbonyl]-N 2 -(tert-butoxycarbonyl)-4-[(methylsulfonyl)oxy]-L-ornithinate (27):

(4R)—N 5 -[(benzyloxy)carbonyl]-N 2 -(tert-butoxycarbonyl)-4-{[(4-methylphenyl)sulfonyl]oxy}-L-ornithinate (28):

(4S)-[ 18 F]-fluoro-L-ornithine (29)

(3R)—N 2 ,N 5 -bis(tert-butoxycarbonyl)-3-fluoro-L-ornithinate (30):

(3R)-3-Fluoro-L-ornithin (31)

methyl-(5S)—N-(tert-butoxycarbonyl)-6-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-L-norleucinate (34)

methyl-(5R)-5-azido-N-(tert-butoxycarbonyl)-6-{[tert-butyl(dimethyl)silyl]oxy}-L-norleucinate (35)

methyl-(5R)-5-azido-N-(tert-butoxycarbonyl)-6-hydroxy-L-norleucinate (36)

(5R)-[ 18 F]-fluoromethyl-L-ornithine (38)

(2S)-5-amino-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-fluoropentanoic acid (43)

benzyl (2S)-5-azido-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-fluoropentanoate (42)

4-( 18 F)fluoro-L-ornithine

3-( 18 F)fluoro-L-ornithine

5-amino-6-( 18 F)fluoro-L-norleucine

8 . A pharmaceutical composition comprising compounds having Formula I according to claim 1 or pharmaceutically acceptable salt of an inorganic or organic acid thereof, a hydrate, a complex, an ester, an amide, a solvate or a prodrug thereof and a pharmaceutical acceptable carrier, diluent, excipient or adjuvant.

9 . A compound of Formula I according to claim 1 for use as reference compound, medicament or radiopharmaceutical.

10 . A compounds of Formula I according to claim 1 for use as imaging agent.

11 . The imaging agent according to claim 10 that is suitable for PET, SPECT or Micro-PET imaging or in combination with other imaging conventional method such as Computer Tomography (CT), and magnetic resonance (MR) spectroscopy of hyperproliferative diseases.

12 . A method for obtaining compounds of Formula I wherein R 7 is a chelator free radionuclide or [ 19 F] by reacting compounds of Formula I wherein R 7 is leaving group with a suitable labeling agent.

13 . A method for obtaining compounds of Formula Ib

by reacting a compound of Formula V

with a labeling agent comprising R 86 to yield a compound of Formula IV,

by substituting said compound of Formula IV with a compound of Formula VI

and

Optionally, deprotecting amine- and/or carboxylic-protecting group;

wherein Formula Ib is defined as bellowed

R 101 , R 102 and R 103 are selected individually and independently from the group comprising

a) hydrogen,

b) ((R 86 —(C 1 -C 6 )alkoxy)aryl)(C 0 -C 10 )alkyl)

c) hydroxyl,

d) C 6 -C 10 aralkyl,

e) C 1 -C 10 alkyl and

f) C 1 -C 10 alkoxy,

with the proviso that compounds of Formula Ib comprise at least one R 86 ,

R 86 is a chelator free radionuclide or [ 19 F], and

R 4 , R 5 , R 6 , and k are defined as above,

wherein Formula V is defined as bellowed

a is an integer from 0 to 5, and

B is a leaving group,

wherein Formula IV is defined as bellowed

a is an integer from 0 to 5,

B is a leaving group, and

R 86 is a chelator free radionuclide or [ 19 F],

wherein Formula VI is defined as bellowed

R 201 , R 202 and R 203 are selected individually and independently from the group comprising

a) hydrogen,

b) ((R 8 -aryl)(C 0 -C 10 )alkyl

c) hydroxyl,

d) C 6 -C 10 aralkyl,

e) C 1 -C 10 alkyl and

f) C 1 -C 10 alkoxy;

R 8 is hydroxyl;

with the proviso that compounds of Formula VI comprise at least one R 8 ,

R 4 , R 5 , R 6 , and k are defined as above.

14 . A compound of Formula Ib

wherein

R 101 , R 102 and R 103 are selected individually and independently from the group comprising

a) hydrogen,

b) ((R 86 —(C 1 -C 6 )alkoxy)aryl)(C 0 -C 10 )alkyl)

c) hydroxyl,

d) C 6 -C 10 aralkyl,

e) C 1 -C 10 alkyl and

f) C 1 -C 10 alkoxy,

with the proviso that compounds of Formula Ib comprise at least one R 86 ,

R 86 is a chelator free radionuclide or [ 19 F], and

R 4 , R 5 , R 6 , and k are defined as above

including all isomeric forms of said compound, including but not limited to enantiomers and diastereoisomers as well as racemic mixtures;

and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof.

15 . A compound of Formula VI

wherein

R 201 , R 202 and R 203 are selected individually and independently from the group comprising

a) hydrogen,

b) ((R 8 -aryl)(C 0 -C 10 )alkyl

c) hydroxyl,

d) C 6 -C 10 aralkyl,

e) C 1 -C 10 alkyl and

f) C 1 -C 10 alkoxy;

R 8 is hydroxyl;

with the proviso that compounds of Formula VI comprise at least one R 8 ,

R 4 , R 5 , R 6 , and k are defined as above

including all isomeric forms of said compound, including but not limited to enantiomers and diastereoisomers as well as racemic mixtures;

and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof.

16 . A kit comprising a sealed vial comprising a predetermined quantity of a compound

a) compound of Formula I according to claim 1 or

b) compound of Formula V

wherein B is a leaving group and a is an integer from 1-5 and a compound of Formula VI

wherein

R 201 , R 202 and R 203 are selected individually and independently from the group comprising

a) hydrogen,

b) ((R 8 )(C 0 -C 10 )alkyl

c) hydroxyl,

d) C 6 -C 10 aralkyl,

e) C 1 -C 10 alkyl and

f) C 1 -C 10 alkoxy;

R 8 is hydroxyl;

with the proviso that compounds of Formula VI comprise at least one R 8 ,

R 4 , R 5 , R 6 , and k are defined as above

including all isomeric forms of said compound, including but not limited to enantiomers and diastereoisomers as well as racemic mixtures;

and any pharmaceutically acceptable salt, ester, amide, complex or prodrug thereof, or a mixture of a) and b).

17 . A method for obtaining compounds having Formula I wherein R 1 -R 6 are defined as above, R 7 is R 15 , R 4 is R 14 and R 5 is R 13 as defined above,

18 . A method for staging, monitoring of hyperproliferative disease progression, or monitoring response to therapy directed to hyperproliferative diseases using compound according claim 1 .