Acetylated Benzothiazolone as Homobivalent SPECT Metallo-Radiopharmaceutical (99m)Tc-(6-AcBTZ)(2)DTPA: Design, Synthesis, and Preclinical Evaluation for Mapping 5-HT(1A/7) Receptors

[Image: see text] Mapping different structural forms of serotonin subtypes 5-HT(1A)–5-HT(7) using a selective-specific ligand with good pharmacokinetics and brain permeability can open avenues for personalized medication in depressed population. Herein, the selective 5-HT(1A/7) antagonist, modified for enhanced brain permeation, is developed as a homobivalent ligand, (6-AcBTZ)(2)DTPA. After in-depth computational studies to probe the binding mechanism, two-step synthesis lead to (6-AcBTZ)(2)DTPA. Biocompatibility studies indicated cytocompatibility with 3.6–1.64% cell death (0.1 mM–1 pM) and hemocompatibility with 2.33% hemolysis of human erythrocytes. When (99m)Tc-radiolabeled in a quantitative yield (98%), a stable preparation was obtained with 7.4 and 3.5% dissociation upon incubation with human serum and excess cysteine. The single-photon-emission computed tomography (SPECT) tracer (99m)Tc-(6-AcBTZ)(2)DTPA showed biphasic clearance (t(1/2, distribution) = 0.5 min and t(1/2, elimination) = 482 min) and maximum brain uptake of 0.42 ± 0.02% ID/g with the regional localization (hippocampus: 11.38% ID/g; cortex: 26.42% ID/g; cerebellum: 25.23% ID/g). Thus, the (99m)Tc-metal-based SPECT neurotracer holds potential for neuroreceptor mapping.