Towards translation of Pb-212 as a clinical therapeutic; getting the lead in!

Targeted alpha-particle therapy offers the potential for more specific tumor cell killing with less damage to surrounding normal tissue than beta-emitters because of the combination of short path length (50-80 mu m) with the high linear energy transfer (100 keV mu m(-1)) of this emission. These physical properties offer the real possibility of targeted (pre-targeted) alpha-therapy suitable for the elimination of minimal residual or micrometastatic disease. Targeted and pre-targeted radioimmunotherapy (RIT) using alpha-emitters such as Bi-212 (T-1/2 = 1.01 h) and Pb-212 (T-1/2 = 10.6 h) has demonstrated significant utility in both in vitro and in vivo model systems. Pb-212, a promising alpha-particle emitting source, is the longer-lived parent nuclide of Bi-212, and serves as an in vivo generator of Bi-212. The radionuclide has been successfully used in RIT and pre-targeted RIT and demonstrated an enhanced therapeutic efficacy in combination with chemotherapeutics, such as gemcitabine and paclitaxel. The following perspective addresses the modes of radionuclide production, radiolabelling and chelation chemistry, as well as the application of Pb-212 to targeted and pre-targeted radiation therapy.