IMAGING AGENTS WITH IMPROVED PHARMACOKINETIC PROFILES

Abstract

The invention relates to compounds suitable for use in an imaging agent said imaging agent showing an improved pharmacokinetic profile.

Claims

1. A compound comprising i) a PEG containing moiety comprising 2 to 30 ethylene glycol units; ii) an imageable moiety useful in PET imaging or SPECT imaging; and a hydrophobic non-peptidic vector moiety not having affinity for the Angiotensin II receptor for delivery of said compound to a disease associated target.

2. (canceled)

3. A compound according to claim 1 wherein said PEG containing moiety is a straight chain PEG containing moiety comprising one or more PEG units.

4. A compound according to claim 1 wherein said PEG containing moiety forms a linker between the imageable moiety and said non-peptidic vector moiety.

5. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

9. A compound according to claim 1 or 4 wherein said non-peptidic vector moiety is a small organic molecule of less than 1000 Da.

10. (canceled)

11. An imaging agent comprising the compound according to claim 1 or 4 and one or more pharmaceutically acceptable adjuvants, excipients or diluents.

12. (canceled)

13. A method of generating contrast enhanced images of a human or non-human animal body, comprising administering a compound according to claim 1.

14. A compound comprising i) a PEG containing moiety comprising 2 to 30 ethylene glycol units; ii) an imageable moiety useful in PET imaging or SPECT imaging; and iii) a hydrophobic non-peptidic vector moiety for delivery of said compound to a disease associated target.

15. A compound comprising: i) a PEG-containing moiety comprising 2 to 30 ethylene glycol units; ii) an imageable moiety; and iii) a hydrophobic non-peptidic vector moiety for delivery of said compound to a disease associated target.

16. A compound according to claim 1, 14, or 15, wherein said imageable moiety is .sup.18F.

17. An imaging agent comprising the compound according to claim 14, 15 or 16 and one or more pharmaceutically acceptable adjuvants, excipients or diluents.

18. A method of generating contrast enhanced images of a human or non-human animal body, comprising administering a compound according to claim 17.

19. A compound according to claim 1, 14 or 15 wherein the PEG containing moiety comprises 2 to 6 ethylene glycol units.

20. A compound according to claim 16 wherein the PEG containing moiety comprises 2 to 6 ethylene glycol units.

21. A compound according to claim 1, 14 or 15 wherein the presence of PEG increases the amount of compound excreted via the renal system.

22. A compound according to claim 16 wherein the presence of PEG increases the amount of compound excreted via the renal system.

23. A compound according to claim 14 or 15 wherein the PEG containing moiety is a straight chain PEG containing moiety comprising one or more PEG units.

24. A compound according to claim 16 wherein said PEG containing moiety is a straight chain PEG containing moiety comprising one or more PEG units.

25. A compound according to claim 14 or 15 wherein the PEG containing moiety forms a linker between said imageable moiety and said non-peptidic vector moiety.

26. A compound according to claim 16 wherein the PEG containing moiety forms a linker between said imageable moiety and said non-peptidic vector moiety.

Description

EXAMPLE 1

Compound 3

[0090] ##STR00004##

[0091] Compound 3 was synthesised using a manual nitrogen bubbler apparatus on a 0.05 mmol scale using Fmoc-protected Rink Amide MBHA resin (Novabiochem), Fmoc-3-iodo-Tyr-OH (Novabiochem), Fmoc PEG propionic acid (Polypure AS, Cat 15137-1195) and compound 1. All acid functions were pre-activated prior to amide bond formation using HATU/DIEA as coupling reagents with DMF as solvent. Reaction steps were analysed by Kaiser test. Fmoc-deprotection was carried out using 20% piperidine in DMF treating first for 5 minutes followed by 40 minutes with fresh piperidine solution. The cleavage from the resin was carried out in TFA containing 2.5% H.sub.2O and 2.5% triisopropylsilane for 2 hours. Crude material was purified by preparative HPLC (column Phenomenex Luna C18(2) 10 nm 25010 mm; solvents A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 20-40% B over 60 min; flow 5.0 ml/min; UV detection at 214 nm) to give 5-10 mg of white solid. Analysis by LC-MS (column Phenomenex Luna C18(2) 3 nm 2.050 mm, solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 10-80% B over 10 min; flow 0.3 ml/min, UV detection at 214 and 254 nm, ESI-MS positive mode) gave peak expected for [MH].sup.+.

EXAMPLE 2

Compound 4

[0092] ##STR00005##

[0093] Compound 4 was synthesised using a manual nitrogen bubbler apparatus on a 0.05 mmol scale using Fmoc-protected Rink Amide MBHA resin (Novabiochem), Fmoc-3-iodo-Tyr-OH (Novabiochem), Fmoc-amino-PEG-diglycolic acid (Polypure AS, Cat. 15131-0295) and compound 1. All acid functions were pre-activated prior to amide bond formation using HATU/DIEA as coupling reagents with DMF as solvent. Reaction steps were analysed by Kaiser test. Fmoc-deprotection was carried out using 20% piperidine in DMF treating first for 5 minutes followed by 40 minutes with fresh piperidine solution. The cleavage from the resin was carried out in TFA containing 2.5% H.sub.2O and 2.5% triisopropylsilane for 2 hours. Crude material was purified by preparative HPLC (column Phenomenex Luna C18(2) 10 nm 25010 mm; solvents A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 20-40% B over 60 min; flow 5.0 ml/min; UV detection at 214 nm) to give 5-10 mg of white solid. Analysis by LC-MS (column Phenomenex Luna C18(2) 3 nm 2.050 mm, solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 10-80% B over 10 min; flow 0.3 ml/min, UV detection at 214 and 254 nm, ESI-MS positive mode) gave peak expected for [MH].sup.+.

EXAMPLE 3

Radiolabelled Compounds 2, 3 and 4

[0094] The identical set of compounds described in Preparation C, Examples 1 and 2 were synthesised where the 3-iodo-tyrosine residue was exchanged for tyrosine. The tyrosine residue was then labelled as the final step using the general procedure described below:

[0095] 10 L 0.1 mM Na.sup.127I (in 0.01M NaOH, 110.sup.9 mol) was added to a vial containing 200 L 0.2M NH.sub.4OAc buffer (pH 4). This solution was added to the vial containing Na.sup.123I (in 0.05M NaOH), which was then transferred to a silanised reaction P15 vial. 5 L (2.510.sup.8 mol) of a freshly prepared peracetic acid solution in water (approx. 5 mM) was added to the reaction vial. 17 L (510.sup.8 mol) of a 3 mM solution of substrate in MeOH was added to the reaction vial and the solution mixed by pipetting. The compounds were purified by HPLC, solvent A: 0.1% TFA in water and solvent B: 0.1% TFA in MeCN using a Phenomenex Luna 5 m C18(2) 1504.6 mm column. The following gradient was applied:

TABLE-US-00001 Time % B 0.0 30 20.0 70 20.20 100 23.20 100 23.70 30 30.0 30

EXAMPLE 4

[0096] Biodistribution of radiolabelled compounds 2, 3 and 4 Radiolabelled compounds 2-4 comprise .sup.127I as an imageable moiety and residue X

##STR00006##

as a non-peptidic vector moiety that is an inhibitor for matrix metalloproteinase. Compounds 2 and 3 do not comprise PEG moities according to the invention and serve as comparison compounds.

[0097] Biodistribution studies were carried out in a Lewis Lung mouse Carcinoma model as described in Bae et al, Drugs Exp Clin Res, 2003; 29 (1): 15-23. Following tail vein injection of the compounds, e the excretion profile was monitored at 5, 30, 60 and 120 minutes. The results are displayed in Table 1.

TABLE-US-00002 TABLE 1 Compound % ID/g liver % ID/g kidney 2 71 7 3 61 20 4 20 70

[0098] From the biodistribution results in table 1 it is apparent, that the presence of a PEG containing moiety that comprises 2 to 50 ethylene glycol units in compound 4i.e. a compound according to claim 1, remarkably improves the biodistribution of the compound in comparison to compounds 2 and 3; the compound is preferably excreted via the renal system.