Prodrugs in site-selective delivery of radiopharmaceuticals

This paper review basic rules for the design of site-selective prodrugs and various modes of their activation with particular emphasis on the applications of prodrugs to targeted delivery of radiopharmaceutical. Although many radiopharmaceuticals are 'targeted' to specific tissues or organs, we will discuss only agents that are either chemically or metabolically transformed producing an active form that is retained by its target. Site-specific prodrugs of diagnostic radiopharmaceuticals are routine in the nuclear medicine applications, but the instances of targeting the radiotherapeutic prodrugs are surprisingly rare. We have concentrated on our own efforts to design and synthesize site-selective prodrugs of 5- [¹²⁵I]iodo-2'deoxyuridine (¹²⁵IUdR) for cancer radiotherapy. The prodrugs of ¹²⁵IUdR for targeted delivery include several derivatives with altered permeability, 3',5'-dioctanoyl, 3',5'-dioleoyl, 3'- and 5'-N-alkyl- dihydropyridyl, 3'- and 5'-N-alkyl-dihydroisoquionolyl, and 3'- and 5'- N- alkyl-dihydroacridinyl esters of ¹²⁵IUdR; polymeric and macromolecular prodrugs of ¹²⁵IUdR for a carrier-mediated or local delivery; metabolically trapped ¹²⁵-IUdR prodrugs; and glycoconjugate prodrugs for oral colon-specific delivery of ¹²⁵IU(D)R. ¹²⁵IU(D)R-5'-β-d- cellobioside, ¹²⁵IU(D)R-5'β-(D)-glucopyranoside, ¹²⁵IU(D)R-5'β-(D)- galactopyranoside and ¹²⁵IU(D)R-5'-β-(D)-glucuronide. We also describe prodrugs of several diagnostic agents in the context of the metabolic trapping as the primary targeting modality. For various diagnostic agents the prodrug target-associated enzymes are discussed and examples of the site- specific release of active agent are given. A brief overview of an emerging role of residualizing labels in radioimmunotherapy is included.