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A 3-Step Pretargeting Strategy to Image Infection

Department of Nuclear Medicine, University Hospital Nijmegen, Nijmegen, The Netherlands

A new 3-step approach to imaging infectious and inflammatory foci was developed and optimized in a rat model. The approach relies on the nonspecific localization of an anti-diethylenetriaminepentaacetic acid (DTPA) antibody in inflamed tissue. In this study, the 3-step strategy was optimized by selecting the most suitable radiolabeled hapten and tuning the dosing schedule. Methods: Wistar rats with Staphylococcus aureus infection in the left calf muscle were primed with the anti-DTPA antibody DTIn-1 (0.67, 2, or 6 nmol per rat). In the second step (1–24 h later), the anti-DTPA activity in the circulation was blocked with unlabeled bovine serum albumin DTPA-In (0.3, 1, or 3 nmol per rat). In the third step (5–30 min later), the radiolabeled hapten (monovalent or bivalent ¹¹¹In-DTPA) was administered. The in vivo distribution of the radiolabel was monitored by scintigraphic imaging and by ex vivo counting of dissected tissues. Results: Scatchard analysis revealed that the affinity of DTIn-1 for bivalent DTPA-¹¹¹In (¹¹¹In-diDTPA) was 6 times higher than the affinity for monovalent ¹¹¹In-DTPA (K_a = 0.87 x 10^-9 mol/L vs. 5.3 x 10^-9 mol/L). The uptake of the bivalent chelate in the abscess was 2.5-fold higher than that of monovalent ¹¹¹In-DTPA. Most important, the bivalent chelate was completely retained in the abscess over time. Using the bivalent chelate, the optimal dosing scheme was determined with respect to the DTIn-1 dose (2 nmol per rat), the blocking agent dose (1 nmol per rat), and radiolabeled chelate dose (40 pmol per rat). The procedure was rapid; the infectious focus was clearly visualized 1 h after injection of the ¹¹¹In-labeled diDTPA, which was 5 h after administration of the anti-DTPA antibody. The nontargeted radiolabel rapidly cleared to the urine, only being retained in the abscess and the kidneys (4–6 percentage injected dose). Finally, an N₂S₂ core was attached to the diDTPA compound, allowing the use of ^99mTc. Conclusion: This 3-step approach enables rapid imaging of infectious foci with minimal uptake in noninflamed tissues.

Key Words: pretargeting • infection imaging • bivalent hapten • anti-DTPA antibody