The imidazo[5,1-d]-1,2,3,5-tetrazine ring-system is hypersensitive to attack by nucleophiles. Therefore, acidic conditions were applied successfully to synthesise new 8-substituted derivatives of the antitumor agents temozolomide (1a) and mitozolomide (1b). The 8-cyanoimidazotetrazines (7a, b) were prepared by dehydration of temozolomide and mitozolomide with thionyl chloride and 7b was converted to the corresponding 8-thioamide (9) with thioacetamide in DMF-HCl. Generation of tertiary carbocations from substituted alkenes by concentrated H 2 SO 4 in the presence of 8-cyanoimidazotetrazines afforded secondary amide congeners (13, 14) of imidazotetrazine-8-carboxamides (Ritter reaction). Peptidic-type coupling of imidazotetrazine-8-carboxylic acids (15a, b) with the protected hydrazine reagent, t-butylcarbazate (BOC-NHNH 2 ), followed by acidic deprotection, gave salts of the carbohydrazides (17, 18) which could be derivatised with aromatic aldehydes. Attempts to synthesise the unknown 8-aminoimidazotetrazine (24) from appropriate 8-substituted substrates by modifications of Hofmann, Curtius and Lossen rearrangements under acidic conditions were all unsuccessful.