Compounds and methods for
The present invention relates to novel compounds suitable for or already radiolabeled with 18 F, methods of making such compounds and use of such compounds for diagnostic imaging. Such labeled compounds are characterized by Formula II, wherein the substituents G, Q, L, Y and U have the meaning as defined in the specification and claims.
1. A compound of Formula A
wherein
-G is selected from —C≡N and —CF 3 , wherein the respective substituent can be in ortho, para or meta position in respect of the K group,
-Q is hydrogen,
-L- is —CO— or —SO 2 —,
Y is a bond or a spacer,
wherein
(a) the spacer is Arg-Ser, Arg-Ava, Lys(Me)2-β-ala, Lys(Me)2-ser, Arg-β-ala, Ser-Ser, Ser-Thr, Arg-Thr, S-alkylcysteine, cysteic acid, thioalkylcysteine (S—S-alkyl) or
wherein k and l are independently selected in the range of from 0 to 4, or
(b) the spacer is a non-amino acid moiety selected from the group consisting of
—NH—(CH 2 ) p —CO—, wherein p is an integer of from 2 to 10,
—NH—(CH 2 —CH 2 —O) q —CH 2 —CH 2 —CO—, wherein q is an integer of from 0 to 5,
—NH-cycloalkyl-CO— wherein cycloalkyl is selected from C 5 -C 8 cycloalkyl, and
—NH-heterocycloalkyl-(CH 2 ) v —CO— wherein heterocycloalkyl is selected from C 5 -C 8 heterocycloalkyl containing carbon atoms and 1, 2, 3 or 4 oxygen, nitrogen or sulfur heteroatoms and v is an integer of from 1 to 4,
U is a targeting agent comprising
(a) a peptide selected from the group consisting of somatostatin, somatostatin receptor specific peptides, neuropeptide Y, neuropeptide Y 1 , bombesin, gastrin, gastrin releasing peptide, epidermal growth factor (EGF of various origin), insulin growth factor (IGF) and IGF-1, integrins (α 3 β 1 , α v β 3 , α v β 5 , αIIb 3 ), LHRH agonists and antagonists, transforming growth factors, particularly TGF-α; angiotensin; cholecystokinin receptor peptides, cholecystokinin (CCK); neurotensin, thyrotropin releasing hormone, pituitary adenylate cyclase activating peptide (PACAP), chemokines, substrates and inhibitors for cell surface matrix metalloproteinase, prolactin, tumor necrosis factor, interleukins (IL-1, IL-2, IL-4 or IL-6), interferons, and vasoactive intestinal peptide (VIP);
(b) a peptide selected from the group consisting of peptides having sequence III or IV:
AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -AA 7 -AA 8 -NT 1 T 2 (type A) III, with:
T 1 =T 2 =H or
T 1 =H, T 2 =OH or
T 1 =CH 3 , T 2 =OH
AA 1 =Gln, Asn, Phe(4-CO—NH 2 )
AA 2 =Trp, D-Trp
AA 3 =Ala, Ser, Val
AA 4 =Val, Ser, Thr
AA 5 =Gly, (N-Me)Gly
AA 6 =His, His(3-Me), (N-Me)His, (N-Me)His(3-Me)
AA 7 =Sta, Statine analogs and isomers, 4-Am,5-MeHpA, 4-Am,5-MeHxA, γ-substituted amino acids
AA 8 =Leu, Cpa, Cba, CpnA, Cha, t-buGly, tBuAla, Met, Nle, iso-Bu-Gly; or
AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -AA 7 -AA 8 -NT 1 T 2 (type B) IV, with:
T 1 =T 2 =H or
T 1 =H, T 2 =OH or
T 1 =CH 3 , T 2 =OH
AA 1 =Gln, Asn or Phe(4-CO—NH 2 )
AA 2 =Trp, D-Trp
AA 3 =Ala, Ser, Val
AA 4 =Val, Ser. Thr
AA 5 =βAla, β 2 - and β 3 -amino acids as shown herein after
wherein SC represents a side chain found in proteinogenic amino acids and homologs of proteinogenic amino acids,
AA 6 =His, His(3-Me), (N-Me)His, (N-Me)His(3-Me)
AA 7 =Phe, Tha, Nal,
AA 8 =Leu, Cpa, Cba, CpnA, Cha, t-buGly, tBuAla, Met, Nle, iso-Bu-Gly; or
(c) wherein U is a NR 7 -peptide, —(CH 2 ) n′ -peptide, —O—(CH 2 ) n′ -peptide or —S—(CH 2 ) n′ -peptide, wherein
n′ is an integer of from 1 to 6,
R 7 is hydrogen or unbranched or branched alkyl and
the peptide is defined in (a) or (b);
X − is CF 3 S(O) 2 O − , C 4 F 9 S(O) 2 O − , iodide anion, bromide anion, chloride anion, perchlorate anion (ClO 4 − ), phosphate anion, trifluoroacetate anion (CF 3 —C(O)O − ), or the anion of another salt of an inorganic or organic acid,
K is N + (R 1 )(R 2 )(R 3 )X − or W,
wherein
R 1 , R 2 and R 3 are each methyl, and
W is 18 F,
or a pharmaceutically acceptable salt of an inorganic or organic acid thereof.
2. The compound according claim 1 , wherein X − is CF 3 —C(O)O − , CF 3 S(O) 2 O − or C 4 F 9 S(O) 2 O − .
3. The compound according to claim 1 , wherein X − is F 3 —C(O)O − or CF 3 S(O) 2 O − .
4. The compound according to claim 1 , wherein Y is Arg-Ser, Arg-Ava, Lys(Me)2-β-ala, Lys (Me)2-ser, Arg-β-ala, Ser-Ser, Ser-Thr, Arg-Thr, S-alkylcysteine, Cysteic acid, thioalkylcysteine (S—S-Alkyl) or
wherein k and l are independently selected in the range of from 0 to 4.
5. The compound according to claim 1 , wherein -Y- is a non-amino acid moiety selected from the group consisting of
—NH—(CH 2 ) p —CO—, wherein p is an integer of from 2 to 10,
—NH—(CH 2 —CH 2 —O) q —CH 2 —CH 2 —CO—, wherein q is an integer of from 0 to 5,
—NH-cycloalkyl-CO— wherein cycloalkyl is selected from C 5 -C 8 cycloalkyl, and
—NH-heterocycloalkyl-(CH 2 ) v —CO— wherein heterocycloalkyl is selected from C 5 -C 8 heterocycloalkyl containing carbon atoms and 1, 2, 3 or 4 oxygen, nitrogen or sulfur heteroatoms and v is an integer of from 1 to 4.
6. The compound according to claim 1 , wherein U is selected from the group consisting of somatostatin, somatostatin receptor specific peptides, neuropeptide Y, neuropeptide Y 1 , bombesin, gastrin, gastrin releasing peptide, epidermal growth factor (EGF of various origin), insulin growth factor (IGF) and IGF-1, integrins (α 3 β 1 , α v β 3 , α v β 5 , αIIb 3 ), LHRH agonists and antagonists, transforming growth factors, particularly TGF-α; angiotensin; cholecystokinin receptor peptides, cholecystokinin (CCK); neurotensin, thyrotropin releasing hormone, pituitary adenylate cyclase activating peptide (PACAP), chemokines, substrates and inhibitors for cell surface matrix metalloproteinase, prolactin, tumor necrosis factor, interleukins (IL-1, IL-2, IL-4 or IL-6), interferons, and vasoactive intestinal peptide (VIP).
7. The compound according to claim 1 , wherein U is selected from the group consisting of bombesin, somatostatin and neuropeptide Y 1 .
8. The compound according to claim 1 , wherein U is selected from the group consisting of peptides having sequence III or IV:
AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -AA 7 -AA 8 -NT 1 T 2 (type A) III, with:
T 1 =T 2 =H or
T 1 =H, T 2 =OH or
T 1 =CH 3 , T 2 =OH;
AA 1 =Gln, Asn, Phe(4-CO—NH 2 )
AA 2 =Trp, D-Trp
AA 3 =Ala, Ser, Val
AA 4 =Val, Ser, Thr
AA 5 =Gly, (N-Me)Gly
AA 6 =His, His(3-Me), (N-Me)His, (N-Me)His(3-Me)
AA 7 =Sta, Statine analogs and isomers, 4-Am,5-MeHpA, 4-Am,5-MeHxA, γ-substituted amino acids
AA 8 =Leu, Cpa, Cba, CpnA, Cha, t-buGly, tBuAla, Met, Nle, iso-Bu-Gly
AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 -AA 7 -AA 8 -NT 1 T 2 (type B) IV, with:
T 1 =T 2 =H or T 1 =H, T 2 =OH or T 1 =CH 3 , T 2 =OH
AA 1 =Gln, Asn or Phe(4-CO—NH 2 )
AA 2 =Trp, D-Trp
AA 3 =Ala, Ser, Val
AA 4 =Val, Ser. Thr
AA 5 =βAla, β 2 - and β 3 -amino acids as shown herein after
wherein SC represents a side chain found in proteinogenic amino acids and homologs of proteinogenic amino acids,
AA 6 =His, His(3-Me), (N-Me)His, (N-Me)His(3-Me)
AA 7 =Phe, Tha, Nal,
AA 8 =Leu, Cpa, Cba, CpnA, Cha, t-buGly, tBuAla, Met, Nle, iso-Bu-Gly.
9. The compound according to claim 1 , wherein U is a NR 7 -peptide, or —(CH 2 ) n′ -peptide, —O—(CH 2 ) n′ -peptide or —S—(CH 2 ) n′ -peptide, wherein n′ is an integer of from 1 to 6, and wherein R 7 is hydrogen or unbranched or branched alkyl.
10. The compound according to claim 9 , wherein R 7 is hydrogen or unbranched or branched C 1 -C 6 alkyl.
11. The compound according to claim 9 , wherein R 7 is hydrogen or methyl.
12. A compound selected from
Ia-1: 4-(Trimethylammonium)-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH 2 (SEQ ID NO: 103),
Ia-2: 4-(Trimethylammonium)-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His(Me)-Sta-Leu-NH 2 (SEQ ID NO: 109),
Ia-3: 4-(Trimethylammonium)-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 110),
Ia-4: 4-(Trimethylammonium)-3-cyano-benzoyl-1,4-cis-Achc-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 111),
Ia-5: 4-(Trimethylammonium)-3-cyano-benzoyl-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 112),
Ia-6: 4-(Trimethylammonium)-3-cyano-benzoyl-AOC-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 113),
Ia-7: 4-(Trimethylammonium)-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Cpa-NH 2 (SEQ ID NO: 114),
Ia-8: 4-(Trimethylammonium)-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH 2 (SEQ ID NO: 115),
Ia-9: 4-(Trimethylammonium)-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 116),
Ia-10: 4-(Trimethylammonium)-3-cyano-benzoyl-Lys (Me)2-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 117),
Ia-11: 4-(Trimethylammonium)-3-cyano-benzoyl-Lys (Me)2-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 118),
Ia-12: 4-(Trimethylammonium)-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH 2 (SEQ ID NO: 119),
Ia-13: 4-(Trimethylammonium)-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH 2 (SEQ ID NO: 120),
Ia-14: 4-(Trimethylammonium)-3-cyano-benzoyl-Lys(Me)2-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-4-AM-5-MeHpA-Leu-NH 2 (SEQ ID NO: 121),
Ia-15: 4-(Trimethylammonium)-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 122),
Ia-16: 4-(Trimethylammonium)-3-cyano-benzoyl-Lys(Me)2-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH 2 (SEQ ID NO: 123),
Ia-17: 4-(Trimethylammonium)-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His-4-Am,5-MeHpA- -Leu-NH 2 (SEQ ID NO: 124),
Ia-18: 4-(Trimethylammonium)-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 125),
Ia-19: 4-(Trimethylammonium)-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 126),
Ia-20: 4-(Trimethylammonium)-3-trifluoromethyl-benzoyl-1,4-cis-Achc-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 127),
Ia-21: 4-(Trimethylammonium)-3-trifluoromethyl-benzoyl-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 128),
Ia-22: 4-(Trimethylammonium)-3-trifluoromethyl-benzoyl-Arg-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH 2 (SEQ ID NO: 129),
Ia-23: 4-(Trimethylammonium)-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-4-Am,5-MeHpA-Cpa-NH 2 (SEQ ID NO: 130),
Ia-24: 4-(Trimethylammonium)-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 131),
Ia-25: 4-(Trimethylammonium)-3-cyano-benzoyl-DOA-Gln-Trp-Ala-Val-Gly-His(3Me)Sta-Leu-NH 2 (SEQ ID NO: 132),
1a-66: 4-(Trimethylammonium)-3-cyano-benzoyl-Ava-ε-c[Lys-(NMe)Phe-1Nal-D-Trp-Lys-Thr] (SEQ ID NO: 133)
1a-67: 4-(Trimethylammonium)-3-cyano-benzoyl-Ava-β-c[Dpr-Met-(NMe)Phe-Tyr-D-Trp-Lys] (SEQ ID NO: 134)
1a-68: 4-(Trimethylammonium)-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Thr-Arg-Cys-Arg-Tyr-NH 2 ] (SEQ ID NO: 135) or
1a-69: 4-(Trimethylammonium)-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Val-Arg-Cys-Arg-Tyr-NH 2 ] (SEQ ID NO: 136).
13. A compound selected from the group consisting of
IIA-a-1: 4-[18]Fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH 2 (SEQ ID NO: 137),
IIA-a-2: 4-[18]Fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His(Me)-Sta-Leu-NH 2 (SEQ ID NO: 138),
IIA-a-3: 4-[18]Fluoro-3-cyano-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 139),
IIA-a-4: 4-[18]Fluoro-3-cyano-benzoyl-1,4-cis-Achc-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 140),
IIA-a-5: 4-[18]Fluoro-3-cyano-benzoyl-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 141),
IIA-a-6: 4-[18]Fluoro-3-cyano-benzoyl-AOC-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 142),
IIA-a-7: 4-[18]Fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-NMeGly-His (3Me)-Sta-Cpa-NH 2 (SEQ ID NO: 143),
IIA-a-8: 4-[18]Fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-FA4-Am,5-MeHpA-Leu-NH 2 (SEQ ID NO: 144),
IIA-a-9: 4-[18]Fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 145),
IIA-a-10: 4-[18]Fluoro-3-cyano-benzoyl-Lys(Me)2-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 146),
IIA-a-11: 4-[18]Fluoro-3-cyano-benzoyl-Lys(Me)2-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 147),
IIA-a-12: 4-[18]Fluoro-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH 2 (SEQ ID NO: 148),
IIA-a-13: 4-[18]Fluoro-3-cyano-benzoyl-Ser-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH 2 (SEQ ID NO: 149),
IIA-a-14: 4-[18]Fluoro-3-cyano-benzoyl-Lys(Me)2-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH 2 (SEQ ID NO: (SEQ ID NO: 150),
IIA-a-15: 4-[18]Fluoro-3-cyano-benzoyl-Arg-Ser-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 151),
IIA-a-16: 4-[18]Fluoro-3-cyano-benzoyl-Lys(Me)2-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH 2 (SEQ ID NO: 152),
IIA-a-17: 4-[18]Fluoro-3-cyano-benzoyl-Ava-Gln-Trp-Ala-Val-Gly-His-4-Am,5-MeHpA-Leu-NH 2 (SEQ ID NO: 153),
IIA-a-18: 4-[18]Fluoro-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-LeuNH 2 (SEQ ID NO: 154),
IIA-a-19: 4-[18]Fluoro-3-trifluoromethyl-benzoyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 155),
IIA-a-20: 4-[18]Fluoro-3-trifluoromethyl-benzoyl-1,4-cis-Achc-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 156),
IIA-a-21: 4-[18]Fluoro-3-trifluoromethyl-benzoyl-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 157),
IIA-a-22: 4-[18]Fluoro-3-trifluoromethyl-benzoyl-Arg-βAla-Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-MeHpA-Leu-NH 2 (SEQ ID NO: 158),
4-[18]Fluoro-3-cyano-benzoyl-(piperidyl-4-carbonyl)-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 213),
4-[18]Fluoro-3-cyano-benzoyl-(piperazin-1-yl-acetyl)-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH 2 (SEQ ID NO: 214),
4-[18]Fluoro-3-cyano-benzoyl-1,4-trans-Achc-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH 2 (SEQ ID NO: 215),
IIA-a-76: 4-[18]Fluoro-3-cyano-benzoyl-Ava-ε-c[Lys-(NMe)Phe-1Nal-D-Trp-Lys-Thr] (SEQ ID NO: 295)
IIA-a-77: 4-[18]Fluoro-3-cyano-benzoyl-Ava-β-c[Dpr-Met-(NMe)Phe-Tyr-D-Trp-Lys] (SEQ ID NO: 296)
IIA-a-78: 4-[18]Fluoro-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Thr-Arg-Cys-Arg-Tyr-NH 2 (SEQ ID NO: 299) and
IIA-a-79: 4-[18]Fluoro-3-cyano-benzoyl-Ava-DCys-Leu-Ile-Val-Arg-Cys-Arg-Tyr-NH 2 (SEQ ID NO: 300).
14. A compound of Formula A
wherein
-G is —C≡N or —CF 3 , wherein the respective substituent —C≡N or CF 3 can be in ortho, para or meta position in respect of the K group,
-Q is hydrogen,
-L- is —CO— or —SO 2 —,
Y is a bond or a spacer,
wherein
(a) the spacer is Arg-Ser, Arg-Ava, Lys(Me)2-β-ala, Lys(Me)2-ser, Arg-β-ala, Ser-Ser, Ser-Thr, Arg-Thr, S-alkylcysteine, cysteic acid, thioalkylcysteine (S—S-alkyl) or
wherein k and l are independently selected in the range of from 0 to 4, or
(b) the spacer is a non-amino acid moiety selected from the group consisting of
—NH—(CH 2 ) p —CO—, wherein p is an integer of from 2 to 10,
—NH—(CH 2 —CH 2 —O) q —CH 2 —CH 2 —CO—, wherein q is an integer of from 0 to 5,
—NH-cycloalkyl-CO— wherein cycloalkyl is selected from C 5 -C 8 cycloalkyl, and
—NH-heterocycloalkyl-(CH 2 ) v —CO— wherein heterocycloalkyl is selected from C 5 -C 8 heterocycloalkyl containing carbon atoms and 1, 2, 3 or 4 oxygen, nitrogen or sulfur heteroatoms and v is an integer of from 1 to 4,
X − is CF 3 S(O) 2 O − , C 4 F 9 S(O) 2 O − , iodide anion, bromide anion, chloride anion, perchlorate anion (ClO 4 − ), phosphate anion, trifluoroacetate anion (CF 3 —C(O)O − ), or the anion of another salt of an inorganic or organic acid,
K is N + (R 1 )(R 2 )(R 3 )X − or W,
wherein
R 1 , R 2 and R 3 are each methyl, and
W is a fluorine isotope, and
U is selected from the group consisting of
Gln-Trp-Ala-Val-NMeGly-His-Sta-
SEQ ID NO: 1
Leu-NH 2
Gln-Trp-Ala-Val-Gly-His(Me)-Sta-
SEQ ID NO: 2
Leu-NH 2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO: 3
Leu-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-
SEQ ID NO: 4
Sta-Leu-NH 2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO: 7
Cpa-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO: 8
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO: 12
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-His-4-Am,5-
SEQ ID NO: 17
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-
SEQ ID NO: 23
4-Am,5-MeHpA-Cpa-NH 2
Gln-Trp-Ala-Val-NMeGly-His-FA02010-
SEQ ID NO: 27
Cpa-NH 2
Gln-Trp-Ala-Val-NMeGly-His-4-Am,5-
SEQ ID NO: 28
MeHpA-tbuGly-NH 2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO: 30
tBuGly-NH 2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-
SEQ ID NO: 32
4-Am,5-MeHpA-Leu-NH 2
Gln-DTrp-Ala-Val-Gly-His-4-Am,5-
SEQ ID NO: 33
MeHpA-tbuGly-NH 2
Gln-DTrp-Ala-Val-Gly-His-4-Am-5-
SEQ ID NO: 34
MeHxA-Cpa-NH 2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO: 35
Cpa-NH 2
Gln-DTrp-Ala-Val-Gly-His-Sta-
SEQ ID NO: 36
tbuAla-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-
SEQ ID NO: 42
Cpa-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-
SEQ ID NO: 43
tBuGly-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO: 46
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO: 48
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-NMeHis-4-Am,5-
SEQ ID NO: 49
MeHpA-Cpa-NH 2
Gln-Trp-Ala-Val-Gly-NMeHis(3Me)-4-
SEQ ID NO: 47
Am,5-MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-NMeHis-4-Am,5-
SEQ ID NO: 50
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-NMeGly-HIs-AHMHxA-
SEQ ID NO: 51
Leu-NH 2
Gln-Trp-Ala-Val-βAla-NMeHis-Tha-
SEQ ID NO: 52
Cpa-NH 2
Gln-Trp-Ala-Val-βAla-NMeHis-Phe-
SEQ ID NO: 53
Cpa-NH 2
Gln-Trp-Ala-Val-βAla-NMeHis-Phe-
SEQ ID NO: 54
Leu-NH 2
Gln-Trp-Ala-Val-βAla-DHis-Phe-
SEQ ID NO: 55
Leu-NH 2
Gln-Trp-Ala-Val-βAla-His-βhLeu-
SEQ ID NO: 56
Leu-NH 2
Gln-Trp-Ala-Val-βAla-His-βhIle-
SEQ ID NO: 57
Leu-NH 2
Gln-Trp-Ala-Val-βAla-His-βhLeu-
SEQ ID NO: 58
tbuGly-NH 2
Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-
SEQ ID NO: 59
Tha-NH 2
Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-
SEQ ID NO: 60
Nle-NH 2
Gln-Trp-Ala-Val-βAla-NMeHis-Phe-
SEQ ID NO: 61
tbuGly-NH 2
Gln-Trp-Ala-Val-βAla-NMeHis-Tha-
SEQ ID NO: 62
tbuGly-NH 2
Gln-Trp-Ala-Val-βAla-His(3Me)-Tha-
SEQ ID NO: 63
tbuGly-NH 2
Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-
SEQ ID NO: 64
Cpa-NH 2
Gln-Trp-Ala-NMeVal-βAla-His-
SEQ ID NO: 65
Phe-Leu-NH 2
Gln-Trp-Ala-Val-βAla-His-NMePhe-
SEQ ID NO: 66
Leu-NH 2
Gln-DTrp-Ala-Val-βAla-His-Phe-
SEQ ID NO: 67
Leu-NH 2
Gln-Trp-DAla-Val-βAla-His-Phe-
SEQ ID NO: 68
Leu-NH 2
Gln-Trp-Ala-DVal-βAla-His-Phe-
SEQ ID NO: 69
Leu-NH 2
Gln-Trp-Ala-Val-βAla-His-DPhe-
SEQ ID NO: 70
Leu-NH 2
Gln-Trp-Ala-Val-βAla-His-βhIle-
SEQ ID NO: 71
tbuGly-NH 2
Gln-Trp-Ala-Val-NMeGly-His-4-Am,5-
SEQ ID NO: 72
MeHpA-Cpa-NH 2
Gln-Trp-Ala-Val-NMeGly-His-Sta-
SEQ ID NO: 73
Cpa-NH 2
Gln-Trp-Ala-Val-NMeGly-His-Sta-
SEQ ID NO: 74
tbuAla-NH 2
Gln-Trp-Ala-Val-NMeGly-His-4-Am,5-
SEQ ID NO: 75
MeHpA-tbuAla-NH 2
Gln-Trp-Ala-Val-His(Me)-Sta-Leu-NH 2
SEQ ID NO: 77
Gln-Trp-Ala-Val-Gly-His(3Me)-
SEQ ID NO: 82
FA4-Am,5-MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO: 90
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-His-4-Am,5-
SEQ ID NO: 91
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-
SEQ ID NO: 101
Am-5-MeHpA-4-amino-5-methyl-
heptanoic acid-Leu-NH 2
and
Gln-Trp-Ala-Val-NMeGly-His(3Me)-4-
SEQ ID NO: 102
Am-5-MeHpA-4-amino-5-methyl-
heptanoic acid-Cpa-NH 2 ,
or a pharmaceutically acceptable salt of an inorganic or organic acid thereof.
15. A method of preparing a compound of claim 1 having chemical Formula A, wherein K═W, and W is fluorine isotope 18 F, according to claim 1 , wherein a compound having general chemical Formula A, wherein K═—N + (R 1 )(R 2 )(R 3 )X − , is labelled with a said fluorine isotope.
16. The method according to claim 15 , comprising the step of coupling a compound having chemical Formula A, wherein K═—N + (R 1 )(R 2 )(R 3 )X − , with a fluorine isotope 18 F to form a compound having general chemical Formula A, wherein K═W, and W is fluorine isotope 18 F, and
wherein K, R 1 , R 2 , R 3 and X − are as defined.
17. A composition comprising a compound of claim 1 having chemical Formula A, wherein K═—N + (R 1 )(R 2 )(R 3 )X − or W, and W is fluorine isotope 18 F, according to claim 1 , and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.
18. A method of diagnostic imaging, comprising introducing into a patient a detectable quantity of a labelled compound of claim 1 having chemical Formula A, wherein K═W, and W is fluorine isotope 18 F, according to claim 1 , or of a pharmaceutically acceptable salt of an inorganic or organic acid thereof.
19. A kit comprising a sealed vial containing a predetermined quantity of a compound of claim 1 having chemical Formula A, wherein K═—N + (R 1 )(R 2 )(R 3 )X − , according to claim 1 , or a pharmaceutically acceptable salt of an inorganic or organic acid thereof.
20. A peptide sequence selected from
Gln-Trp-Ala-Val-NMeGly-His-Sta-
SEQ ID NO: 1
Leu-NH 2
Gln-Trp-Ala-Val-Gly-His(Me)-Sta-
SEQ ID NO: 2
Leu-NH 2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO: 3
Leu-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-
SEQ ID NO: 4
Sta-Leu-NH 2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO: 7
Cpa-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO: 8
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO: 12
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-His-4-Am,5-
SEQ ID NO: 17
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-
SEQ ID NO: 23
4-Am,5-MeHpA-Cpa-NH 2
Gln-Trp-Ala-Val-NMeGly-His-FA02010-
SEQ ID NO: 27
Cpa-NH 2
Gln-Trp-Ala-Val-NMeGly-His-4-Am,5-
SEQ ID NO: 28
MeHpA-tbuGly-NH 2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO: 30
tBuGly-NH 2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-
SEQ ID NO: 32
4-Am,5-MeHpA-Leu-NH 2
Gln-DTrp-Ala-Val-Gly-His-4-Am,5-
SEQ ID NO: 33
MeHpA-tbuGly-NH 2
Gln-DTrp-Ala-Val-Gly-His-4-Am-5-
SEQ ID NO: 34
MeHxA-Cpa-NH 2
Gln-Trp-Ala-Val-NMeGly-His(3Me)-Sta-
SEQ ID NO: 35
Cpa-NH 2
Gln-DTrp-Ala-Val-Gly-His-Sta-
SEQ ID NO: 36
tbuAla-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-
SEQ ID NO: 42
Cpa-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-
SEQ ID NO: 43
tBuGly-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO: 46
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO: 48
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-NMeHis-4-Am,5-
SEQ ID NO: 49
MeHpA-Cpa-NH 2
Gln-Trp-Ala-Val-Gly-NMeHis(3Me)-4-
SEQ ID NO: 47
Am,5-MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-NMeHis-4-Am,5-
SEQ ID NO: 50
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-NMeGly-HIs-AHMHxA-
SEQ ID NO: 51
Leu-NH 2
Gln-Trp-Ala-Val-βAla-NMeHis-Tha-
SEQ ID NO: 52
Cpa-NH 2
Gln-Trp-Ala-Val-βAla-NMeHis-Phe-
SEQ ID NO: 53
Cpa-NH 2
Gln-Trp-Ala-Val-βAla-NMeHis-Phe-
SEQ ID NO: 54
Leu-NH 2
Gln-Trp-Ala-Val-βAla-DHis-Phe-
SEQ ID NO: 55
Leu-NH 2
Gln-Trp-Ala-Val-βAla-His-βhLeu-
SEQ ID NO: 56
Leu-NH 2
Gln-Trp-Ala-Val-βAla-His-βhIle-
SEQ ID NO: 57
Leu-NH 2
Gln-Trp-Ala-Val-βAla-His-βhLeu-
SEQ ID NO: 58
tbuGly-NH 2
Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-
SEQ ID NO: 59
Tha-NH 2
Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-
SEQ ID NO: 60
Nle-NH 2
Gln-Trp-Ala-Val-βAla-NMeHis-Phe-
SEQ ID NO: 61
tbuGly-NH 2
Gln-Trp-Ala-Val-βAla-NMeHis-Tha-
SEQ ID NO: 62
tbuGly-NH 2
Gln-Trp-Ala-Val-βAla-His(3Me)-Tha-
SEQ ID NO: 63
tbuGly-NH 2
Gln-Trp-Ala-Val-βAla-His(3Me)-Phe-
SEQ ID NO: 64
Cpa-NH 2
Gln-Trp-Ala-NMeVal-βAla-His-
SEQ ID NO: 65
Phe-Leu-NH 2
Gln-Trp-Ala-Val-βAla-His-NMePhe-
SEQ ID NO: 66
Leu-NH 2
Gln-DTrp-Ala-Val-βAla-His-Phe-
SEQ ID NO: 67
Leu-NH 2
Gln-Trp-DAla-Val-βAla-His-Phe-
SEQ ID NO: 68
Leu-NH 2
Gln-Trp-Ala-DVal-βAla-His-Phe-
SEQ ID NO: 69
Leu-NH 2
Gln-Trp-Ala-Val-βAla-His-DPhe-
SEQ ID NO: 70
Leu-NH 2
Gln-Trp-Ala-Val-βAla-His-βhIle-
SEQ ID NO: 71
tbuGly-NH 2
Gln-Trp-Ala-Val-NMeGly-His-4-Am,5-
SEQ ID NO: 72
MeHpA-Cpa-NH 2
Gln-Trp-Ala-Val-NMeGly-His-Sta-
SEQ ID NO: 73
Cpa-NH 2
Gln-Trp-Ala-Val-NMeGly-His-Sta-
SEQ ID NO: 74
tbuAla-NH 2
Gln-Trp-Ala-Val-NMeGly-His-4-Am,5-
SEQ ID NO: 75
MeHpA-tbuAla-NH 2
Gln-Trp-Ala-Val-His(Me)-Sta-Leu-NH 2
SEQ ID NO: 77
Gln-Trp-Ala-Val-Gly-His(3Me)-
SEQ ID NO: 82
FA4-Am,5-MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-Am,5-
SEQ ID NO: 90
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-His-4-Am,5-
SEQ ID NO: 91
MeHpA-Leu-NH 2
Gln-Trp-Ala-Val-Gly-His(3Me)-4-
SEQ ID NO: 101
Am-5-MeHpA-4-amino-5-methyl-
heptanoic acid-Leu-NH 2
or
Gln-Trp-Ala-Val-NMeGly-His(3Me)-4-
SEQ ID NO: 102
Am-5-MeHpA-4-amino-5-methyl-
heptanoic acid-Cpa-NH 2 .
21. The compound of claim 5 , wherein v is an integer 1 or 2.
22. A compound of claim 14 , wherein W is 18 F.
23. A method of claim 18 , wherein the diagnostic imaging is by positron emission tomography (PET).