US 9,809,624 B2
Neurotensin analogues for radioisotope targeting to neurotensin receptor-positive tumors
Anne Gruaz, Paris (FR); Didier Pelaprat, Paris (FR); Jacques Barbet, Nantes (FR); and Dirk Tourwe, Brussels (BE)
Assigned to INSERM (Institut National de la Sante et de la Recherche Medicale), Paris (FR); and IASON GmbH, Graz-Seiersberg (AT)
Appl. No. 13/384,418
Filed by Anne Gruaz, Paris (FR); Didier Pelaprat, Paris (FR); Jacques Barbet, Nantes (FR); and Dirk Tourwe, Brussels (BE)
PCT Filed Jul. 16, 2010, PCT No. PCT/EP2010/060293
§ 371(c)(1), (2), (4) Date May 1, 2012,
PCT Pub. No. WO2011/006985, PCT Pub. Date Jan. 20, 2011.
Claims priority of application No. 09305679 (EP), filed on Jul. 16, 2009.
Prior Publication US 2012/0207676 A1, Aug. 16, 2012
Int. Cl. A61K 51/00 (2006.01); A61M 36/14 (2006.01); C07K 7/08 (2006.01); A61K 51/08 (2006.01); A61K 38/00 (2006.01)
CPC C07K 7/083 (2013.01) [A61K 51/08 (2013.01); A61K 51/085 (2013.01); A61K 51/088 (2013.01); A61K 38/00 (2013.01)] 11 Claims
 
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(CH2—NH)-(L)Arg, and ψ(CH2—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-NH2 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-NH2 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—(CH2)n—CO— wherein n is from 1 to 5, and
an acetyl group is coupled to the remaining NH2 of Aa6,
and wherein
said analogue, when in solution at physiological pH and at physiological temperature, has at most two positive charges.