Acetylated Benzothiazolone as Homobivalent SPECT Metallo-Radiopharmaceutical ^99mTc-(6-AcBTZ)₂DTPA: Design, Synthesis, and Preclinical Evaluation for Mapping 5-HT_1A/7 Receptors

Abstract

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.

Synthesis and Biological Evaluation of 99mTc-Labeled Phenylpiperazine Derivatives as Selective Serotonin-7 Receptor Ligands for Brain Tumor Imaging

“…Both categories of radiotracers can afford information on the grading and prognosis of GBM, but amino acid tracers, with a lower uptake in normal brain tissue, are more appropriate for the description of tumor extent, treatment planning, or follow-up than glucose metabolism tracers. − Compared with PET, SPECT has a lower cost and wider availability. Currently, to the evaluation of GBM, several SPECT radiotracers such as Thallium-201 ( 201 Tl), [ 99m Tc]-Sestamibi ([ 99m Tc]­MIBI), 99m Tc-hexamethylpropyleneamine-oxime ([ 99m Tc]-HMPAO), and [ 99m Tc]-Tetrofosmin were widely employed. ,− Today, for in vivo 5-HT 7 R imaging, there is no clinical radiotracer, and some PET tracers such as [ 11 C]-Cimbi-717 or [ 18 F]-2FP3 have been evaluated in cats or pigs with promising outcomes, but they could not produce a specific signal in nonhuman primates. , Other radioligands were not successful even in the early stages of evaluation; − hence, one attractive method is to prepare imaging probes for a specific targeting of the 5-HT 7 receptors with an overexpression in GBM. , …”