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Improved gastrin releasing peptide compounds

A compound, targeting peptide technology, applied in the field of neogastrin-releasing peptide compounds

Inactive Publication Date: 2007-01-17
BRACCO IMAGINIG SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Conversely, too rapid clearance of radiopharmaceuticals from the bloodstream by the kidneys is also undesirable if longer diagnostic imaging is required or radiation therapy with high tumor uptake

Method used

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  • Improved gastrin releasing peptide compounds
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  • Improved gastrin releasing peptide compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0356] The following examples are provided as examples of different methods that can be used to prepare various compounds of the invention. In each example, there is a compound identified with a single bold capital letter (eg, A, B, C) that is related to a corresponding compound identically labeled in the figure.

[0357] General experiment

[0358] A. Definitions of other abbreviations used

[0359] The following common abbreviations are used throughout this specification:

[0360] 1,1-Dimethylethoxycarbonyl (Boc or Boc);

[0361] 9-fluorenylmethoxycarbonyl (Fmoc);

[0362] Allyloxycarbonyl (Aloc);

[0363] 1-Hydroxybenzotriazole (HOBt or HOBT);

[0364] N,N'-diisopropylcarbodiimide (DIC);

[0365] N-methylpyrrolidone (NMP);

[0366] Acetic anhydride (Ac 2 O);

[0367] (4,4-Dimethyl-2,6-dioxocyclohexylene-1-yl)-3-methylbutyl (iv-Dde);

[0368] Trifluoroacetic acid (TFA);

[0369] Reagent B (TFA:H 2 O: phenol: triisopropylsilane, 88:5:5:2);

[0...

Embodiment I-

[0418] Example I- Figure 1A -B

[0419] Synthetic L62

[0420] Overview: as Figure 1A As shown in -B, prepare L62 with the following steps:

[0421] Hydrolysis of (3β,5β)-3-aminocholan-24-oic acid methyl ester A with NaOH gave the corresponding acid B, which was then reacted with Fmoc-Cl to give intermediate C. Using octapeptide Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH 2 (BBN[7-14][SEQ ID NO:1]) functionalized Rink amide resin was sequentially reacted with C, Fmoc-glycine and DOTA tri-tert-butyl ester. After cleavage and deprotection with Reagent B, the crude was purified by preparative HPLC to afford L62. Overall yield: 2.5%. More details are provided below:

[0422] A. Rink amide resin functionalized with bombesin [7-14], (A)

[0423] In a solid-phase peptide synthesis vessel (see Appendix No.1), combine Fmoc-amino acid (24mmol), N-hydroxybenzotriazole (HOBt) (3.67g; 24mmol) and N,N′-diisopropylcarbon Diimine (DIC) (3.75 mL; 24 ...

Embodiment II-

[0434] Example II- Figure 2A -F

[0435] Synthesis of L70, L73, L74, L115 and L116

[0436] Overview: The product is obtained by the following method: the octapeptide Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH loaded on the Rink amide resin 2 (BBN[7-14][SEQ ID NO: 1]) (with appropriate side chain protection) was coupled to different linkers and then functionalized with DOTA tri-tert-butyl ester. After cleavage and deprotection with reagent B, the final product was purified by preparative HPLC. Overall yield 3-9%.

[0437] A. Synthesis of L70 ( Figure 2A ):

[0438]Resin A (0.5 g; 0.3 mmol) was shaken with 50% morpholine in DMA (7 mL) in a solid phase peptide synthesis vessel for 10 minutes, the solution was emptied and fresh 50% morpholine in DMA (7 mL) was added. Morpholine. The suspension was stirred for 20 minutes, then the solution was emptied and the resin was washed with DMA (5 x 7 mL). Fmoc-4-aminobenzoic acid (0.43 g; 1.2 mmol), HOBT...

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Abstract

New and improved compounds for use in radiodiagnostic imaging or radiotherapy having the formula M-N-O-P-G, wherein M is the metal chelator (in the form complexed with a metal radionuclide or not), N-O-P is the linker, and G is the GRP receptor targeting peptide. Methods for imaging a patient and / or providing radiotherapy to a patient using the compounds of the invention are also provided. A method for preparing a diagnostic imaging agent from the compound is further provided. A method for preparing a radiotherapeutic agent is further provided.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Application 10 / 828,925, filed April 20, 2004, which is a continuation-in-part of International Application PCT / US03 / 041328, filed December 24, 2003, which claimed January 13, 2003 Priority of filed US application 10 / 341,577. The contents of all of these applications are hereby incorporated by reference in their entirety. field of invention [0003] The present invention relates to novel gastrin releasing peptide (GRP) compounds useful as diagnostic imaging agents or radiotherapeutic agents. These GRP compounds are labeled with radionuclides or labels detectable by in vivo optical imaging and include the use of a novel linker between the label and the targeting peptide to provide improved pharmacokinetics. Background of the invention [0004] The use of radiopharmaceuticals (eg diagnostic imaging agents, radiother...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/00A61M36/14
Inventor E·卡佩勒蒂L·拉图塔K·E·林德E·马里奈利P·南加潘N·拉尤R·E·斯文森M·推德尔K·拉迈林加姆
Owner BRACCO IMAGINIG SPA
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