Development of 134Ce/134La radiopharmaceuticals as positron emitting analogues of alpha emitting radionuclides

Actinium-225 (t_1/2 = 9.9 days) and thorium-227 (t_1/2 = 18.7 days) are the preeminent candidates for Targeted Alpha Therapy (TAT), where alpha-emitting radionuclides are chemically coupled to targeting vectors in order to deliver high linear energy transfer (LET) radiation to nearby tissue. Since ²²⁵Ac and ²²⁷Th do not produce a signal that can be detected by Positron Emission Tomography (PET), positron-emitting surrogate radionuclides will have to be developed to allow for patient-specificay efficacy and dosimetry of radiopharmaceuticals incorporating ²²⁵Ac or ²²⁷Th. The ¹³⁴Ce/¹³⁴La (t_1/2 = 3.16 days/6.45 minutes) in vivo generator system has been hypothesized to be a surrogate radionuclide for both of these alpha-emitters since its oxidation state can be stabilized to match the oxidation state of ²²⁵Ac and ²²⁷Th in physiological conditions and has a suitably long half-life, allowing for the tracing of large macromolecules' in vivo biodistribution and pharmacokinetics. This talk will discuss the incorporation of ¹³⁴Ce/¹³⁴La in antibody drug conjugates (Trastuzumab-DOTA-¹³⁴Ce(III)). The utility of this system will be displayed through in vivo MicroPET imaging of the candidate molecule in a SK-OV-3 tumor bearing NOD SCID mouse model.

Biodistribution of Trastuzumab-DOTA-¹³⁴Ce over 6 days after injection.