Condensation of tert-butyl 4-fluoro-3-(bromomethyl)benzoate (I) with N-Boc-1,3-propanediamine (II) afforded the aminomethyl benzoate derivative (III). This was coupled with N-Cbz-L-aspartic acid beta-methyl ester (IV), yielding amide (V). After hydrogenolysis of the carbobenzoxy protecting group of (V), the resultant fluoro amine (VI) was cyclized to the benzodiazepinone (VII) upon treatment with 2,6-di-tert-butylpyridine in hot NMP. Acidic cleavage of both the tert-butyl ester and the N-Boc groups of (VII), followed by reprotection of the amine with Boc2O, furnished the N-Boc acid (VIII). This was then coupled to 2-(methylaminomethyl)benzimidazole (IX) to afford, after acidic Boc group cleavage, the amino amide (X).
Coupling between gamma-tert-butoxy glutamic acid (XI) and gamma-tert-butoxy-N-Cbz-glutamic acid succinimidyl ester (XII) produced the protected dipeptide (XIII). This was further coupled to the intermediate amine (X) to furnish the corresponding amide (XIV). After hydrogenolysis of the N-Cbz protecting group of (XIV), the resultant amine (XV) was acylated with tetraazacyclododecanetetraacetic acid tri-tert-butyl ester (XVI), yielding the amide adduct (XVII).
Basic hydrolysis of the methyl ester group of (XVII) and subsequent acidic cleavage of the tert-butyl esters gave rise to the hexacarboxylic acid derivative (XVIII). Finally, complexation of (XVIII) with 177LuCl3 furnished the title lutetium complex.