Radiolabeled bombesin-derived compounds for in vivo imaging of gastrin-releasing peptide receptor (grpr) and treatment of grpr-related disorders

Patent metadata

Field	Value
Publication number	US-2021402016-A1
Application number	US-201917293455-A
Country	US
Kind code	A1
Filing date	Nov 13, 2019
Priority date	Nov 13, 2018
Publication date	Dec 30, 2021
Grant date	—

Abstract

There is provided bombesin-derived compounds of Formula Ia (R X -L-Xaa 1 -Gln-Trp-Ala-Val-Xaa 2 -His-Xaa 3 -ψ-Xaa 4 -NH 2 ). R X comprises a radionuclide chelator or a trifluoroborate-containing prosthetic group. L is a linker. Xaa 1 is D-Phe, Cpa (4-chlorophenylalanine), D-Cpa, Tpi (2,3,4,9-tetrahydro-1H-pyrido[3,4b]indol-3-carboxylic acid), D-Tpi, Nal (naphthylalanine), or D-Nal. Xaa 2 is Gly, N-methyl-Gly or D-Ala. Xaa 3 is Leu, Pro, D-Pro, or Phe. Xaa 4 is Pro, Phe, Tac (thiazolidine-4-carboxylic acid), Nle (norleucine), 4-oxa-L-Pro (oxazolidine-4-carboxylic acid). The symbol ψ represents a reduced peptide bond between Xaa 3 and Xaa 4 in which ψ is CH 2 —N when Xaa 4 is Pro, Tac or 4-oxa-L-Pro, or ψ is CH 2 N(R) when Xaa 4 is Phe or Nle wherein R is H or C 1 -C 5 linear or branched alkyl. There is also provided the use of such compounds as imaging agents or therapeutic agents.

First claim

1 . A compound of Formula Ia
R X -L-Xaa 1 -Gln-Trp-Ala-Val-Xaa 2 -His-Xaa 3 -ψ-Xaa 4 -NH 2   (Ia)
wherein: R X comprises a radionuclide chelator or a trifluoroborate-containing prosthetic group; L is a linker; Xaa i is D-Phe, Cpa (4-chlorophenylalanine), D-Cpa, Tpi (2,3,4,9-tetrahydro-1H-pyrido[3,4b]indol-3-carboxylic acid), D-Tpi, Nal (naphthylalanine), or D-Nal; Xaa 2 is Gly, N-methyl-Gly or D-Ala; Xaa 3 is Leu, Pro, D-Pro, or Phe; Xaa 4 is Pro, Phe, Tac (thiazolidine-4-carboxylic acid), Nle (norleucine), 4-oxa-L-Pro (oxazolidine-4-carboxylic acid); and ψ represents a reduced peptide bond between Xaa 3 and Xaa 4 in which ψ is

when Xaa 4 is Pro, Tac or 4-oxa-L-Pro, or W is —CH2N(R)— when Xaa 4 is Phe or Nle wherein R is H or C 1 -C 5 linear or branched alkyl.

2 . The compound of claim 1 , wherein R X comprises the radionuclide chelator.

3 . The compound of claim 2 , wherein the radionuclide chelator is selected from the group consisting of: DOTA and derivatives; DOTAGA; NOTA; NODAGA; NODASA; CB-DO2A; 3p-C-DEPA; TCMC; DO3A; DTPA and DTPA analogues optionally selected from CHX-A″-DTPA and 1B4M-DTPA; TETA; NOPO; Me-3,2-HOPO; CB-TE1A1P; CB-TE2P; MM-TE2A; DM-TE2A; sarcophagine and sarcophagine derivatives optionally selected from SarAr, SarAr-NCS, diamSar, AmBaSar, and BaBaSar; TRAP; AAZTA; DATA and DATA derivatives; H2-macropa or a derivative thereof; H 2 dedpa, H 4 octapa, H 4 py4pa, H 4 Pypa, H 2 azapa, H 5 decapa, and other picolinic acid derivatives; CP256; PCTA; C-NETA; C-NE3TA; HBED; SHBED; BCPA; CP256; YM103; desferrioxamine (DFO) and DFO derivatives; H 6 phospa; a trithiol chelate; mercaptoacetyl; hydrazinonicotinamide; dimercaptosuccinic acid; 1,2-ethylenediylbis-L-cysteine diethyl ester; methylenediphosphonate;
hexamethylpropyleneamineoxime; and hexakis(methoxy isobutyl isonitrile).

4 . The compound of claim 2 , wherein the radionuclide chelator is selected from DOTA and DOTA derivatives.

5 . The compound of any one of claim 2 , wherein R X further comprises a radiometal, a radionuclide-bound metal, or a radionuclide-bound metal-containing prosthetic group, and wherein the radiometal, the radionuclide-bound metal, or the radionuclide-bound metal-containing prosthetic group is chelated to the radionuclide-chelator complex.

6 . The compound of claim 5 , wherein the radiometal, the radionuclide-bound metal, or the radionuclide-bound metal-containing prosthetic group is: 68 Ga, 61 Cu, 64 Cu, 67 Cu, 67 Ga 111 In, 44 Sc, 86 Y, 89 Zr, 90 Nb, 177 Lu, 117m Sn, 165 Er, 90 Y, 227 Th, 225 Ac, 213 Bi, 212 Bi, 72 As, 77 As, 211 At, 203 Pb, 212 Pb, 47 Sc, 166 Ho, 188 Re, 186 Re, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 114m In, 94m Tc, 99m Tc, 149 Tb, 152 Tb, 155 Tb, 161 Tb, or [ 18 F]AlF.

7 . The compound of claim 5 , wherein the radiometal, the radionuclide-bound metal, or the radionuclide-bound metal-containing prosthetic group is: 68 Ga, 61 Cu, 64 Cu, 67 Cu, 67 Ga, 111 In, 44 Sc, 86 Y, 177 Lu, 90 Y, 149 Tb, 152 Tb, 155 Tb, 161 Tb, 225 Ac, 213 Bi, or 212 Bi.

8 . The compound of claim 1 , wherein R X comprises one or more than one trifluoroborate-containing prosthetic group.

9 . The compound of claim 8 , wherein R X comprises one or more than one R 1 R 2 BF 3 group, wherein:
each R 1 is independently

wherein each R 3 is independently absent,

and
each R 2 BF 3 is independently:

wherein each R 4 is independently a C 1 -C 5 linear or branched alkyl group and each R 5 is independently a C 1 -C 5 linear or branched alkyl group,

in which the R in each pyridine substituted —OR, —SR, —NR—, —NHR or —NR 2 is independently a branched or linear C 1 -C 5 alkyl.

10 . The compound of claim 8 , wherein R X comprises one or more than one R 1 R 2 BF 3 , wherein:
each R 1 is independently

wherein each R 3 is independently absent,

and
each R 2 BF 3 is independently:

wherein each R 4 is independently a C 1 -C 5 linear or branched alkyl group and each R 5 is independently a C 1 -C 5 linear or branched alkyl group,

in which the R in each pyridine substituted —OR, —SR, —NR—, —NHR or —NR 2 is independently a branched or linear C 1 -C 5 alkyl.

11 . The compound of claim 8 , wherein the R X comprises a single R 1 R 2 BF 3 group.

12 . The compound of claim 8 , wherein the R X comprises two R 1 R 2 BF 3 groups.

13 . The compound of claim 8 , wherein the trifluoroborate-containing prosthetic group comprises 18 F.

14 . The compound of claim 8 , wherein the linker is a peptide linker (Xaa 5 ) 1-4 , wherein each Xaa 5 is independently a proteinogenic or non-proteinogenic amino acid residue.

15 . The compound of claim 1 , wherein the linker is a peptide linker (Xaa 5 ) 1-4 , wherein each Xaa 5 is independently a proteinogenic amino acid residue or is a non-proteinogenic amino acid residue, wherein each peptide backbone amino group is independently optionally methylated, and wherein each non-proteinogenic amino acid residue is independently selected from the group consisting of a D-amino acid of a proteinogenic amino acid, N ε , N ε , N ε -trimethyl-lysine, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), ornithine (Orn), homoarginine (hArg), 2-amino-4-guanidinobutyric acid (Agb), 2-amino-3-guanidinopropionic acid (Agp), 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp), (3-alanine, 4-aminobutyric acid, 5-aminovaleric acid, 6-aminohexanoic acid, 7-aminoheptanoic acid, 8-aminooctanoic acid, 9-aminononanoic acid, 10-aminodecanoic acid, 2-aminooctanoic acid, 2-aminoadipic acid (2-Aad), 3-aminoadipic acid (3-Aad), cysteic acid, tranexamic acid, p-aminomethylaniline-diglycolic acid (pABzA-DIG), 4-amino-i-carboxymethyl-piperidine (Pip), NH 2 (CH 2 ) 2 O(CH 2 ) 2 C(O)OH, NH 2 (CH 2 ) 2 [O(CH 2 ) 2 ] 2 C(O)OH (dPEG2), NH 2 (CH 2 ) 2 [O(CH 2 ) 2 ] 3 C(O)OH, NH 2 (CH 2 ) 2 [O(CH 2 ) 2 ] 4 C(O)OH, NH 2 (CH 2 ) 2 [O(CH 2 ) 2 ] 5 C(O)OH, and NH 2 (CH 2 ) 2 [O(CH 2 ) 2 ] 6 C(O)OH.

16 . The compound of claim 1 , wherein the linker is p-aminomethylaniline-diglycolic acid (pABzA-DIG), 4-amino-(1-carboxymethyl)piperidine (Pip), 9-amino-4,7-dioxanonanoic acid (dPEG2) or 4-(2-aminoethyl)-1-carboxymethyl-piperazine (Acp).

17 . (canceled)

Assignees

• Provincial Health Services Authority

Inventors

• Benard Francois
• Lin Kuo-Shyan
• Rousseau Etienne
• Zhang Zhengxing
• Lau Joseph
• Bratanovic Lvica
• Zeisler Jutta

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K51/08

  Peptides, e.g. proteins {, carriers being peptides, polyamino acids, proteins} · CPC title

• C07K7/086 Primary

  Bombesin; Related peptides (having more than 20 amino acids C07K14/57572) · CPC title

• A61K51/088 Primary

  conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10) · CPC title