Imidazoles tritium-labelled

H]GR 168320 was developed as a (stably labelled) tritiated H3 antagonist and evaluated for its in vitro use as a radioligand for the H3 receptor [29], As has been shown for thioperamide, the tritium labels at the 2 and 5 position of the imidazole moiety and at the 4 position of the piperidine moiety are sensitive to exchange with hydrogen from the storage solution. [3H]GR 168320 is labelled at the cyclohexane, by a catalytic reduction with 3H2, no details about the synthesis have been published (scheme 11). [3H]GR 168320 was isolated with a specific activity of 4.8 Ci/mmol. 

A large part (65%) of the label located at the C(2)(H) position in 152 is probably due to base-catalysed hydrogen isotope exchange still operating even in the presence of prereduced Pt02. The specific activities of the tritium-labelled epoxides by the same procedure are lower than for the imidazoles. The specific activities of the tritiated imidazoles can be improved by using tritiated water of higher specific activity. 

There are examples of the uncatalyzed exchange with HHO at the a-positions of steroidal ketones . The ketone functions were immediately subjected to synthetic transformations in order to prevent tritium loss by back-exchange. The C2 positions of imidazole-containing pharmaceuticals have been similarly exchanged in this case, the half-time for loss of the tritium label was determined to be 2.4 days at 37 °C and pH 7, adequate for the intended study. This figure is similar to that measured for [imidazole-2- H]histidine, namely 2.8 days at 37 °C and pH 8.2. 

The classical histamine H3 antagonist thioperamide has been labelled and evaluated as radioligand for the H3 receptor by Alves-Rodrigues et al [27], [3H]thioperamide was synthesised from [3H]4-(lH-imidazol-4-yl)piperidine, labelled with tritium in the 2 or 5 position of the imidazole and at the 4 position of the piperidine, and cyclohexylisothiocyanate (scheme 10) [28], It was purified with a semipreparative HPLC method and isolated with a specific activity of 6 Ci/mmol. 

The tritium at this position is much more stable than it would be if the labels were at the imidazole moiety. The compound proved to be a good radioligand for in vitro studies of the H3 receptor, (see the chapter "Radioligand binding studies for the H3 receptor" by F.P. Jansen et at). 

---