Heavy vitamin B12 derivatives
The invention discussed in this application relates to vitamin B12-based compounds that are useful as quantitative standards, particularly for the assessment of vitamin B12 deficiency.
1. A heavy vitamin B12 having a mass shift of at least +8 over unlabelled vitamin B12, wherein the heavy vitamin B12 comprises eight or nine 13 C atoms and the eight or nine 13 C atoms are located in the dimethylbenzimidazole moiety of the vitamin.
2. The heavy vitamin B12 of claim 1 , comprising eight 13 C atoms.
3. The heavy vitamin B12 of claim 1 , comprising nine 13 C atoms.
4. The heavy vitamin B12 of claim 1 , wherein the heavy vitamin B12 has a mass shift of from +8 to +11 over unlabelled vitamin B12.
5. The heavy vitamin B12 of claim 4 , wherein the heavy vitamin B12 has a mass shift of +8 over unlabelled vitamin B12.
6. The heavy vitamin B12 of claim 4 , wherein the heavy vitamin B12 has a mass shift of +9 over unlabelled vitamin B12.
7. The heavy vitamin B12 of claim 4 , wherein the heavy vitamin B12 has a mass shift of +10 over unlabelled vitamin B12.
8. The heavy vitamin B12 of claim 4 , wherein the heavy vitamin B12 has a mass shift of +11 over unlabelled vitamin B12.
9. The heavy vitamin B12 of claim 1 , wherein the heavy vitamin B12 is a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof:
wherein
R is 5′-deoxyadenosyl, OH, H 2 O, CH 3 , or CN.
10. The heavy vitamin B12 of claim 9 , wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzenesulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaieic, hydroiodic, phenylacetic, alkanoic, sodium, potassium, calcium, aluminum, lithium, and ammonium salts.
11. The heavy vitamin B12 of claim 1 , wherein the heavy vitamin B12 further comprises one or more 2 H atoms.
12. The heavy vitamin B12 of claim 11 , wherein the heavy vitamin B12 further comprises two 2 H atoms.
13. The heavy vitamin B12 of claim 11 , wherein the one or more 2 H atoms are also located in the dimethylbenzimidazole moiety of the vitamin.
14. The heavy vitamin B12 of claim 1 , wherein at least 90% of the molecules in the heavy vitamin B12 have a single mass shift.
15. The heavy vitamin B12 of claim 14 , wherein at least 95% of the molecules in the heavy vitamin B12 have a single mass shift.
16. A pharmaceutical composition comprising the heavy vitamin B12 of claim 1 , and one or more pharmaceutically acceptable carrier substances, diluents or excipients.
17. A method of assessing a patient for vitamin B12 deficiency, the method comprising:
administering to a patient an effective amount of the heavy vitamin B12 of claim 1 , or a pharmaceutical composition thereof,
obtaining a biological fluid sample from the patient, and
analysing the sample to determine the quantity of the heavy vitamin B12 in the sample.
18. The method of claim 17 , wherein the biological fluid sample is a blood sample.
19. The method of claim 18 , wherein the red blood cells are separated from the serum.
20. The method of claim 17 , wherein the heavy vitamin B12 is administered parenterally or orally.