Linker Chemistry in Radiopharmaceutical Design

Over the last half century, molecularly targeted bioconjugates have revolutionized nuclear medicine. An array of vectors, ranging from small molecule peptidomimetics to macromolecular immunoglobulins, has been radiolabeled with radionuclides to create probes that have been deployed in both the laboratory and the clinic for positron emission tomography (PET), single photon emission computed tomography (SPECT), and radiopharmaceutical therapy. Generally speaking, these compounds have four constituent parts: (i) a targeting vector; (ii) a radionuclide; (iii) a labeling moiety, such as a chelator for radiometals or a prosthetic group for radiohalogens; and (iv) a linker that connects the vector and the labeling moiety. Each of these parts is critical to the performance of the radiopharmaceutical, but the importance of the former─the linker─can be lost in the shadow of its flashier teammates. Strictly speaking, the linker's job is simple: stably connect the vector and the radiolabeling moiety so that they do not become detached <i>in vivo</i>. However, recent years have been a witness to increasing efforts to exploit the properties of linkers to improve the pharmacokinetic profiles of radiopharmaceuticals. Along these lines, the most common strategies are predicated on changing the structure of the linker to alter the hydrophobicity and bioavailability of the probe, but several other innovative approaches have emerged as well, including those that rely upon stimuli for the <i>cleavage</i> of the linker. In this review, we will offer a systematic and critical discussion of the ways in which radiopharmaceutical chemists have leveraged linker chemistry to optimize the <i>in vivo</i> performance of probes for nuclear imaging and therapy, with a particular emphasis on nascent methodologies. We will also explore the lessons that other fields, most notably the development of antibody-drug conjugates, can offer the radiopharmaceutical community with respect to the design and implementation of new linker technologies.