Synthesis of tritiated Cyclosporin A and FK‐506 by metal‐catalyzed hydrogen isotope exchange

Abstract

SummaryTritium-labeled Cyclosporin A (I) and FK-506 (II) have been prepared using a metalcatalysed hydrogen isotope exchange procedure and high specific activity tritiated water. Specific activities of the labeled compounds were 0.15 and 0.59 TBq/mmol, respectively.

Tritiated dihydro compounds employed as radioligand surrogates

“…Its total synthesis was accomplished soon thereafter by Merck chemists in 1989 . Since then, 18 has been a synthetic target of radiochemists and was directly tritiated by the Myasoedov group in collaboration with Novartis scientists, obtaining [ 3 H] 18 at nearly 16 Ci/mmol . No detailed information was reported regarding tritium location in the product except that numerous positions appeared to be radiolabeled when examined by tritium NMR.…”

“…A second prominent immunosuppressant macrocycle is cyclosporin A ( 20 ), isolated from the fungus Tolypocladium inflatum Gams , but unlike tacrolimus, it is a peptide . There have been several approaches to tritium labeling 20 itself, including direct high temperature exchange, the ‘tritium deficiency’ method as well as catalytic tritium dehalogenation of a bromo precursor . However, these procedures provided [ 3 H] 20 at only low to modest specific activity and were somewhat tedious.…”

Preparation of Tritium‐Labeled Compounds by Isotope Exchange Reactions

“…Additional factors that may in some cases improve outcomes are the use of a secondary support (Norit, fibrous carbon, Al 2 O 3 , BaSO 4 or CaCO 3 ) mechanically mixed with the catalyst-substrate blend 236,237 and other additives 238,239 . Nevertheless, in spite of the accumulation of a large body of empirical data and mechanistic and theoretical study, there exists no standard set of reaction conditions, nor is it yet possible to make informed selection of optimum conditions based on compound structure.…”

27 Radiochemistry and radiopharmaceuticals

“…The standard procedures now used to produce tritium-labelled molecules have been reviewed. 49 The rather general method of metal catalysed hydrogen exchange using tritiated water has been used 50 to label cyclosporine A and FK-506, but it is more usual to place the tritium atom at a specific location in the target molecule. This can be done by displacing a halogen atom using tritium gas, as in the preparation of 51 2,3,4,9-tetrahydro-1H-carbazoles 52 or neurokinini-1 receptor ligands.…”