Neurotensin analogues for radioisotope targeting to neurotensin receptor-positive tumors

1. A neurotensin analogue, or a salt thereof, of formula (I)

X-L-Aa8-Aa9-(L)Pro-Aa11-Aa12-(L)Leu  (I)

wherein

Aa8 is NMe-(L)Arg, Nme-(D)Arg, NMe-(L)Lys or NMe-(D)Lys, and

the sequence Aa9-(L)Pro-Aa11-Aa12-(L)Leu differs from (L)Arg-(L)Pro-(L)Tyr-(L)Ile-(L)Leu by at least one substitution in the amino acid sequence, the substitution(s) being selected from:

Aa9 is selected from the group consisting of (L)Lys, ψ(CH 2 —NH)-(L)Arg, and ψ(CH 2 —NH)-(L) Lys,

Aa11 is selected from the group consisting of (D)Tyr, (L)Dmt and (D)Dmt, and

Aa12 is selected from the group consisting of (L)Tle, (L)Leu and (L)Val,

X is a poly(aminocarboxylate) chelating moiety selected from the group consisting of:

i) diethylenetriamine pentaacetic acid (DTPA) and its derivatives,

ii) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and its derivatives,

iii) 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and its derivatives,

iv) 1,4,8,11-tetraazacyclododecane-1,4,8,11-tetraacetic acid (TETA) and its derivatives,

v) 1,4,7,10-tetraazacyclotridecane-N,N′,N″,N′″-tetracetic acid (TITRA) and its derivatives,

vi) triethylenetetramine hexaacetic acid (TTHA) and its derivatives,

vii) 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and its derivatives, and

viii) 1,4,7-triazacyclononane-1-succinic acid-4,7-diacetic acid (NODASA) and its derivatives, and

L is a linker which separates X and Aa8, and said linker L is selected from the group consisting of

-Aa6-Aa7-, wherein X is coupled to Aa6 via the ε-NH 2 of the lateral chain of Aa6, or

-L1-Aa6-Aa7-, wherein X is coupled to L1, and L1 is coupled to Aa6 via the ε-NH 2 of the lateral chain of Aa6 or via the α-NH2 of Aa6,

wherein

Aa6 is selected from the group consisting of (D)Lys, and (L)Lys,

Aa7 is selected from the group consisting of (L)Pro, and (D)Pro,

and L1 is —NH—(CH 2 ) n —CO— wherein n is from 1 to 5, and

an acetyl group is coupled to the remaining NH 2 of Aa6,

and wherein

said analogue, when in solution at physiological pH and at physiological temperature, has at most two positive charges.

2. The neurotensin analogue, or the salt thereof, according to claim 1 , wherein Aa8 is NMe-(L)Arg, and

Aa12 is (L)Tle.

3. The neurotensin analogue, or the salt thereof, according to claim 1 , wherein the neurotensin analogue is selected from the group consisting of the following formulas:

Ac-(L)Lys 6 (DTPA)-(L)Pro 7 -NMeArg 8 -(L)Arg 9 -(L)Pro 10 -(L)Tyr 11 -(L)Tle 12 -(L)Leu 13

Ac-(L)Lys 6 (DOTA)-(L)Pro 7 -NMe(L)Arg 8 -(L)Arg 9 -(L)Pro 10 -(L)Tyr 11 -(L)Tle 12 -(L)Leu 13

Ac-(L)Lys 6 (Ahx-DOTA)-(L)Pro 7 -NMeArg 8 -(L)Arg 9 -(L)Pro 10 -(L)Dmt 11 -(L)Tle 12 -(L)Leu 13 .

4. A pharmaceutical composition comprising the neurotensin analogue according to claim 1 and a pharmaceutically acceptable carrier.

5. The neurotensin analogue according to claim 1 , further comprising a detectable element which forms a complex with the poly(aminocarboxylate) chelating moiety X, wherein the detectable element is selected from the group consisting of 111 In, 67 Ga, 68 Ga, 64 Cu and 44 Sc.

6. The neurotensin analogue according to claim 5 , wherein said detectable element is Gd 3+ .

7. The neurotensin analogue according to claim 5 , wherein said detectable element is Eu 3+ .

8. The neurotensin analogue according to claim 1 , further comprising a cytotoxic element that forms a complex with the chelating moiety X, wherein said cytotoxic element is selected from the group consisting of 90 Y, 177 Lu, 67 Cu, 47 Sc, 212 Bi, 213 Bi, 226 Th, 111 In and 67 Ga.

9. The neurotensin analogue, or the salt thereof, according to claim 1 , wherein X represents a poly(aminocarboxylate) chelating moiety selected from the group consisting of: diethylenetriamine pentaacetic acid (DTPA), S-2(4-Aminobenzyl)-diethylenetriamine pentaacetic acid (p-NH2-Bn-DTPA), (R)-2-Amino-3-(4-aminophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid, [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid, and 2-(4-Isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid (p-SCN-Bn-DTPA).

10. The neurotensin analogue, or the salt thereof, according to claim 1 , wherein X represents a poly(aminocarboxylate) chelating moiety selected from the group consisting of: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclo-dodecane tetraacetic acid (p-aminobenzyl-DOTA), and S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (p-SCN-Bn-DOTA).

11. The neurotensin analogue, or the salt thereof, according to claim 1 , wherein X represents a poly(aminocarboxylate) chelating moiety selected from the group consisting of: 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), S-2-(4-aminobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-NH2-Bn-NOTA) and S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA).