Several radiolabeled forms of Org-5222 and its metabolite Org-30526 have been synthesized: 1) [5-36Cl]-Org-5222: The nitration of trans-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole (I) with HNO3/H2SO4 gives the 5-nitro derivative (II), which is reduced with H3PO3 - Pd/C in methanol to the corresponding amino derivative (III). Finally, this compound is deaminated with NaNO2 and [36Cl]-HCl in the presence of powdered Cu.

2) [3a-3H]-Org-5222: The equilibration of cis-11-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[ 4,5-c]pyrrol-1-one (IV) with [3H]-H2O by means of NaOCH3 in hot HMPT gives the tritiated trans-amide (V) (along with the cis-isomer, which is separated by HPLC). The trans-amide (V) is then reduced with LiAlH4/AlCl3 in ethyl ether.

3) [11-3H]-Org-5222: The iodination of Org-5222 (VI) with N-iodosuccinimide (NIS) and trifluoromethanesulfonic acid in CH2Cl2 gives the 11-iodo derivative (VII), which is then reduced with 3H2 and Pd/C in ethanol. 4) [7,11-3H2]-Org-5222: The nitration of Org-5222 (VI) with HNO3/H2SO4 gives the 7,11-dinitro derivative (VIII), which is reduced with Fe/acetic acid to the 7,11-diamino compound (IX). The reaction of (IX) with NaNO2/HCl in the presence of KI yields the 7,11-diiodo derivative (X), which is then reduced with 3H2 and Pd/C in ethanol as before. 5) [7,11-3H2]-Org-30526: The reaction of [7,11-3H2]- Org-5222 with ethyl chloroformate in refluxing toluene gives the carbamate (XI), which is then hydrolyzed under strongly basic conditions.

6) [11-3H]-Org-30526: The reaction of Org-5222 (VI) with ethyl chloroformate in refluxing toluene gives the carbamate ester (XII), which is hydrolyzed with HBr to afford Org-30526 (XIII). The iodination of (XIII) with NIS and trifluoromethanesulfonic acid yields the 11-iodo derivative (XIV), which is finally reduced with 3H2 and Pd/C in ethanol.

7) [12b-14C]-Org-5222: The condensation of labeled sarcosine methyl ester (XVI) (prepared from sarcosine (XV) with SOCl2 and methanol) with 2-(5-chloro-2-phenoxyphenyl)acetyl chloride (XVIII) (prepared from the corresponding acid (XVII) and SOCl2) yields the acylated sarcosine (XIX), which is cyclized by means of potassium tert-butoxide in toluene to the pyrrolidinedione (XX). A further cyclization of (XX) with polyphosphoric acid affords [3a-14C]-11-chloro-2-methyl-2,3-dihydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (XXI), which is reduced with Mg in methanol to the trans-isomeric amide (XXII) (along with the cis-isomer, which is separated by HPLC). Finally, the amide (XXII) is reduced with LiAlH4/AlCl3 in ethyl ether.