Leukocyte receptor-binding radiopharmaceuticals for infection and inflammation scintigraphy.

On pages 786–793 of this issue of The Journal of Nuclear Medicine, van Eerd et al. (1) present the results of their investigations into the localization mechanisms of 111In-labeled leukotriene B4 antagonist (DPC11870), a recently developed radiopharmaceutical (2) for infection and inflammation scintigraphy. Belonging to the growing group of receptor-binding radiopharmaceuticals, designed to label leukocytes in vivo, DPC11870 is distinguished by high affinity to the leukotriene B4 receptor that is abundantly expressed on the granulocyte cell surface. The rationale for in vivo labeling is to alleviate the labor intensity and the hazard of cross infection during the handling of autologous blood in the course of 111In and 99mTc ex vivo white blood cell (WBC) labeling. The genesis of this group can be traced to the development (about 2 decades ago) of monoclonal antibodies raised against an antigen present on leukocytes. That initial effort (3) eventually culminated in the recent clinical introduction of 99mTc-fanolesomab in the United States. It soon became clear that, all other factors being equal, using smaller carrier molecules should be better, for they are generally easier to manufacture, radiolabel, and deliver to the target, and they clear from the nontarget tissues by faster excretion. The initial success in that pursuit was marked by the development of an antibody fragment with good binding to antigen-90 on the granulocyte surface (4). At about the same time, small peptide radiopharmaceuticals began to stimulate interest (5). An improved understanding of small peptide interactions at sites of inflammation and infection has created a fertile knowledge base of such radiopharmaceutical candidates, whereas advances in peptide synthesis and radiolabeling chemistry made this area of research into a fruitful endeavor (6). Even smaller nonpeptide leukocyte-binding molecules, such as the frontrunner DPC11870, soon received attention, holding yet greater promise for infection and inflammation scintigraphy (7). The ultimate catalyst for progress in this field, however, is the clinical demand for accurate and easy-to-use radiopharmaceuticals specifically designed for particular clinical presentations of suspected infection or inflammation. An understanding of granulocyte kinetics is an essential prerequisite for the proper interpretation of the work done by van Eerd et al. (1) or, for that matter, any investigation that concerns WBC scintigraphy. Three physiologic compartments are involved in such kinetics: first, the pool in the marrow undergoing development and release with average granulocyte residence of 10 d; second, the total blood pool, which comprises the circulating and so-called marginating granulocyte subpools; and third, the graveyards within which the blood granulocytes are physiologically destroyed at a rate that leads to their entire replacement within the circulation every 10 h. The inflammatory lesion itself constitutes the fourth compartment into which granulocytes from the second compartment migrate. Because the bone marrow is an important component of both the second and the third compartments (pooling granulocytes to the same extent as the spleen and destroying them with an efficiency comparable to that of the spleen and liver), it has a more complex kinetic role in the setting of myeloid-targeting agents, such as 111In-DPC11870, compared with cells conventionally labeled ex vivo. Therefore, it is not surprising that 111InDPC11870 shows prominent bone marrow uptake, reflecting the location of the great majority ( 80%) of the myeloid cell mass and indicating that the LTB4 receptor is expressed early in granulocyte maturation. For the same reason, the monoclonal antibodies to granulocyte receptors have to some extent all given prominent images of bone marrow and indeed at one stage were exploited for imaging cancer metastases in the marrow that predate bone secondaries. Circulating granulocytes would be preferentially targeted if the radiopharmaceutical were directed toward a receptor that is expressed only on mature cells. Indeed, the ideal granulocyte-seeking agent would avidly target only cells that had migrated across the vascular endothelium and express a unique postmigration receptor. This seems to be an element in the repertoire of 99mTc-sulesomab (8) and effectively is the mechanism underlying 18F-FDG uptake in inflammation. The kinetics of 111InDPC11870 are not, therefore, straightforward, and 2 important considerations emerge. First, one would not expect similar kinetics for cells labeled in vivo and for those labeled with the compound ex vivo because the role of the first compartment is eliminated with respect to the latter. Second, proof of the concept of labeled cells trafficking from compartment 1 to the lesion, Received Dec. 31, 2004; revision accepted Mar. 8, 2005. For correspondence or reprints contact: Mark Tulchinsky, MD, Department of Radiology, H066, Penn State Milton S. Hershey Medical Center, Penn State College of Medicine, 500 University Dr., Hershey, PA 17033. E-mail: mtulchin@psu.edu