Radiolabeled melanocortin 1 receptor-specific alpha-melanocyte-stimulating hormone analogues for imaging or therapy

Patent metadata

Field	Value
Publication number	US-2024350681-A1
Application number	US-202418640256-A
Country	US
Kind code	A1
Filing date	Apr 19, 2024
Priority date	May 23, 2018
Publication date	Oct 24, 2024
Grant date	—

Abstract

A compound is provided comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1RTP), a radiolabeling group, and a linker joining the MC1RTP to the radiolabeling group. The MC1RTP is linear or cyclized, and comprises a sequence of Formula I or Formula II: Xaa1-Xaa2a-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7a (I) or Xaa1-Xaa2b-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7b (I). Xaa1 is L- /D-Nle, L-/D-Nle, L-/D-Ala, L-/D-Leu, L-/D-Ile, D-Ile, L-/D-Cys, L-/D-Met, L-/D-Phe, L-/D-Trp, L-/D-Val, L-/D-Nal, L-/D-2-Nal, Gly, L-/D-α-aminobutryic acid, L-/D-norvaline, or L-/D-homonorleucine. Xaa2a and Xaa7b are L-/D-Cys, L-/D-Asp, L-/D-Glu, L-/D-2-Aad, L-/D-3-Aad, L-/D-Pra, L-/D-Hpg, or L-/D-Bpg. Xaa2b and Xaa7a are L-/D-Cys, L-/D-Lys, L-/D-Orn, L-/D-Dab, L-/D-Dap, L-/D-Lys(N3), L-/D-Om(N3), L-/D-Dab(N3), L-/D-Dap(N3), L-/D-2-(5′-azidopentyl)alanine, or L-/D-2-(6′-azidohexyl)alanine. Xaa3 is L-/D-His, Pro, beta-(1,2,3-triazol-4-yl)-L-alanine, beta-(1,2,3-triazol-4-yl)-D-alanine, 1,2,4-triazole-3-alanine, or 1,2,4-triazole-3-D-N alanine. Xaa4 is L-/D-Phe, L-/D-2-Nal, L-/D-Phe(4-F), L-/D-Phe(4-Cl), L-/D-Phe(4-Br), L-/D-Phe(4-I), L-/D-Phe(4-NH2), or L-/D-Phe(4-NO2). Xaa5 is L-/D-Arg, L-/D-hArg), Leu, L-/D-Agb, or L-/D-Agp. Xaa6 is L-/D-Trp, L-/D-Phe, L-/D-Trp(5-Br), L-/D-Trp(5-OCH3), L-/D-Trp(6-F), L-/D-Trp(5-OH) or L-/D-Trp(CHO). One or more amino acid residues of the MC1RTP is alpha N-methylated, wherein 1, 2, 3 or 4 of Xaa3, Xaa5, Xaa6 and Xaa7a is alpha N-methylated or wherein 1, 2, 3 or 4 of Xaa3, Xaa5, Xaa6 and Xaa2b is alpha N-methylated. The linker comprises an albumin-binding group.

First claim

1 - 27 . (canceled)

28 . A compound comprising a melanocortin 1 receptor (MC1R) targeting peptide (MC1RTP), a radiolabeling group, and a linker joining the MC1RTP to the radiolabeling group, wherein:
the MC1RTP is linear or cyclized, and comprises a sequence of Formula I or Formula II,
Xaa 1 -Xaa 2a -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7a   (I); or

Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7b   (II);

Xaa 1 is norleucine (Nle), D-Nle, Ala, D-Ala, Leu, D-Leu, Ile, D-Ile, Cys, D-Cys, Met, D-Met, Phe, D-Phe, Trp, D-Trp, Val, D-Val, 3-(1-naphthyl)alanine (Nal), D-Nal, 3-(2-naphthyl)alanine (2-Nal), D-2-Nal, Gly, α-aminobutryic acid, D-α-aminobutryic acid, norvaline, D-norvaline, homonorleucine, or D-homonorleucine; Xaa 2a is Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-aminoadipic acid (2-Aad), D-2-Aad, 3-aminoadipic acid (3-Aad), D-3-Aad, propargylglycine (Pra), D-Pra, homopropargylglycine (Hpg), D-Hpg, beta-homopropargylglycine (Bpg) or D-Bpg; Xaa 2b is Cys, D-Cys, Lys, D-Lys, Ornithine (Orn), D-Orn, 2,4-diaminobutyric acid (Dab), D-Dab, 2,3-diaminopropionic acid (Dap), D-Dap, Lys(N 3 ), D-Lys(N 3 ), Orn(N 3 ), D-Orn(N 3 ), Dab(N 3 ), D-Dab(N 3 ), Dap(N 3 ), D-Dap(N 3 ), 2-(5′-azidopentyl)alanine, D-2-(5′-azidopentyl)alanine, 2-(6′-azidohexyl)alanine or D-2-(6′-azidohexyl)alanine; Xaa 3 is His, D-His, Pro, beta-(1,2,3-triazol-4-yl)-L-alanine, beta-(1,2,3-triazol-4-yl)-D-alanine, 1,2,4-triazole-3-alanine, or 1,2,4-triazole-3-D-alanine; Xaa 4 is Phe, D-Phe, 2-Nal, D-2-Nal, Phe(4-F), D-Phe(4-F), Phe(4-Cl), D-Phe(4-Cl), Phe(4-Br), D-Phe(4-Br), Phe(4-I), D-Phe(4-I), Phe(4-NH 2 ), D-Phe(4-NH 2 ), Phe(4-NO 2 ), or D-Phe(4-NO 2 ); Xaa 5 is Arg, D-Arg, homoarginine (hArg), D-hArg, Leu, D-Leu, 2-amino-4-guanidinobutyric acid (Agb), D-Agb, 2-amino-3-guanidinopropionic acid (Agp) or D-Agp; Xaa 6 is Phe, D-Phe, Trp, D-Trp, Trp(5-Br), D-Trp(5-Br), Trp(5-OCH 3 ), D-Trp(5-OCH 3 ), Trp(6-F), D-Trp(6-F), Trp(5-OH), D-Trp(5-OH), Trp(CHO), or D-Trp(CHO); Xaa 7a is Cys, D-Cys, Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, D-Dap, Lys(N 3 ), D-Lys(N 3 ), Orn(N 3 ), D-Orn(N 3 ), Dab(N 3 ), D-Dab(N 3 ), Dap(N 3 ), D-Dap(N 3 ), 2-(5′-azidopentyl)alanine, D-2-(5′-azidopentyl)alanine, 2-(6′-azidohexyl)alanine or D-2-(6′-azidohexyl)alanine; Xaa 7b is Cys, D-Cys, Asp, D-Asp, Glu, D-Glu, 2-Aad, D-2-Aad, 3-Aad, D-3-Aad, Pra, D-Pra, Hpg, D-Hpg, Bpg or D-Bpg; the MC1RTP is optionally C-terminally amidated; and Xaa 5 and Xaa 7a in Formula I are alpha N-methylated and Xaa 5 and Xaa 7b in Formula II are alpha N-methylated.

29 . The compound of claim 28 , wherein the MC1RTP is cyclized by:
(i) a lactam bridge connecting Xaa 2a to Xaa 7a in Formula I or connecting Xaa 2b to Xaa 7b in Formula II, formed by connecting the side chain of Asp, D-Asp, Glu, D-Glu, 2-Aad, or D-2-Aad with the side chain of Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap, or D-Dap; (ii) a 1,2,3-triazole connecting Xaa 2a to Xaa 7a in Formula I or connecting Xaa 2b to Xaa 7b in Formula II, formed by connecting the side chains of Pra, D-Pra, Hpg, D-Hpg, Bpg or D-Bpg with Lys(N 3 ), D-Lys(N 3 ), Orn(N 3 ), D-Orn(N 3 ), Dab(N 3 ), D-Dab(N 3 ), Dap(N 3 ), D-Dap(N 3 ), 2-(5′-azidopentyl)alanine, D-2-(5′-azidopentyl)alanine, 2-(6′-azidohexyl)alanine or D-2-(6′-azidohexyl)alanine; or (iii) a disulfide bridge connecting Xaa 7a to either Xaa 1 or Xaa 2a in Formula I when Xaa 7a is Cys and one or both of Xaa 1 and Xaa 2a is Cys, or connecting Xaa 7b to either Xaa 1 or Xaa 2b in Formula II when Xaa 7b is Cys and one or both of Xaa 1 and Xaa 2b is Cys.

30 . The compound of claim 28 , wherein each of Xaa 1 , Xaa 2a , Xaa 2b , Xaa 3 , Xaa 5 , Xaa 6 , Xaa 7a , and Xaa 7b is an L-amino acid and Xaa 4 is a D-amino acid.

31 . The compound of claim 28 , wherein the MC1RTP comprises Nle-cyclo[Asp-His-(D-Phe)-Arg-Trp-Lys], wherein the MC1RTP is optionally C-terminally amidated, and wherein Xaa 5 and Xaa 7a in Formula I is alpha N-methylated.

32 . The compound of claim 29 , wherein the linker comprises an albumin-binding group

33 . The compound of claim 28 , wherein the MC1RTP is C-terminally amidated.

34 . The compound of claim 28 , wherein the linker is either:
a C 1 -C 120 alkylenyl which is: linear or branched; saturated or unsaturated; or acyclic or cyclic; or a C 1 -C 120 alkylenyl where one or more of the carbon atoms is independently replaced with a heteroatom, which is: linear or branched; saturated or unsaturated; or acyclic or cyclic.

35 . The compound of claim 32 , wherein:
the linker is a linear peptide of 3 to 6 amino acid residues, -Xaa 8 -Xaa 9 -(Xaa 10 ) 1-4 -, wherein Xaa 8 , Xaa 9 , and Xaa 10 are each independently an amino acid and wherein the radiolabeling group and the albumin-binding group are bonded to the free N-terminus of Xaa 8 and the side chain of Xaa 9 , respectively, or the radiolabeling group and the albumin-binding group are bonded to the side chain of Xaa 9 and the free N-terminus of Xaa 8 , respectively; or the linker is a branched peptide of 3 to 6 amino acid residues, -Xaa 9 (Xaa 8 )-(Xaa 10 ) 1-4 -, wherein Xaa 8 and Xaa 10 are each independently an amino acid and Xaa 9 is Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap or D-Dap; and wherein the C-terminus of Xaa 8 forms an amide with the side chain of Xaa 9 ; and wherein the radiolabeling group and the albumin-binding group are bonded to the free N-termini of Xaa 8 and Xaa 9 , respectively, or the radiolabeling group and the albumin-binding group are bonded to the free N-termini of Xaa 9 and Xaa 8 , respectively.

36 . The compound of claim 32 , wherein:
either:
the linker comprises a linear peptide, -Xaa 8 -Xaa 9 -Xaa 10 -, wherein Xaa 8 , Xaa 9 , and Xaa 10 are each independently an amino acid and wherein the radiolabeling group and the albumin-binding group are bonded to the free N-terminus of Xaa 8 and the side chain of Xaa 9 , respectively, or the radiolabeling group and the albumin-binding group are bonded to the side chain of Xaa 9 and the free N-terminus of Xaa 8 , respectively;
or: the linker comprises a branched peptide, -Xaa 9 (Xaa 8 )-Xaa 10 -, wherein Xaa 8 is an amino acid; Xaa 9 is Lys, D-Lys, Orn, D-Orn, Dab, D-Dab, Dap or D-Dap; and Xaa 10 is —N(H)R 2 R 3 R 2 C(O)—, in which each R 2 is independently absent, methylene or ethylene, and R 3 is —(CH 2 ) 1-11 — or

in which each X 1 is independently carbon or nitrogen;
wherein the C-terminus of Xaa 8 forms an amide with the side chain of Xaa 9 ; and wherein the radiolabeling group and the albumin-binding group are bonded to the free N-termini of Xaa 8 and Xaa 9 , respectively, or the radiolabeling group and the albumin-binding group are bonded to the free N-termini of Xaa 9 and Xaa 8 , respectively.

37 . The compound of claim 36 , wherein Xaa 10 is 4-amino-1-carboxymethyl-piperidine (Pip), 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp), or —N(H)—(CH 2 ) 3-15 C(O)—.

38 . The compound of claim 35 , wherein Xaa 8 is Gly, Glu, D-Glu, Asp, D-Asp, 2-Aad, D-2-Aad, 3-Aad, or D-3-Aad.

39 . The compound of claim 28 , wherein Xaa 5 is N-Me-Arg.

40 . The compound of claim 28 , wherein Xaa 7a as N-Me-Lys.

41 . The compound of claim 35 , wherein the albumin-binding group has the following structure:

wherein each R 4 is independently H, halogen, C 1 -C 5 alkyl, C 1 -C 5 alkoxyl or nitro group; and wherein the albumin-binding group is coupled to the α-amino gro

Assignees

• Provincial Health Services Authority

Inventors

• Bénard François
• Lin Kuo-Shyan
• Zhang Chengcheng
• Zhang Zhengxing
• Zeisler Jutta

Classifications

• A61K51/0482

  chelates from cyclic ligands, e.g. DOTA · CPC title

• A61K47/08

  containing oxygen, {e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides} · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K14/6955

  with at least 1 amino acid in D-form · CPC title

• C07K7/56

  the cyclisation not occurring through 2,4-diamino-butanoic acid · CPC title