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. 2019 Jun 10;4(6):10044-10055.
doi: 10.1021/acsomega.9b00633. eCollection 2019 Jun 30.

Acetylated Benzothiazolone as Homobivalent SPECT Metallo-Radiopharmaceutical 99mTc-(6-AcBTZ)2DTPA: Design, Synthesis, and Preclinical Evaluation for Mapping 5-HT1A/7 Receptors

Preeti Jha  1   2 , Shubhra Chaturvedi  2 , Anju  2 , Ankur Kaul  2 , Nidhi Jain  1 , Anil K Mishra  2
Affiliations

Acetylated Benzothiazolone as Homobivalent SPECT Metallo-Radiopharmaceutical 99mTc-(6-AcBTZ)2DTPA: Design, Synthesis, and Preclinical Evaluation for Mapping 5-HT1A/7 Receptors

Preeti Jha et al. ACS Omega. .

Abstract

Mapping different structural forms of serotonin subtypes 5-HT1A-5-HT7 using a selective-specific ligand with good pharmacokinetics and brain permeability can open avenues for personalized medication in depressed population. Herein, the selective 5-HT1A/7 antagonist, modified for enhanced brain permeation, is developed as a homobivalent ligand, (6-AcBTZ)2DTPA. After in-depth computational studies to probe the binding mechanism, two-step synthesis lead to (6-AcBTZ)2DTPA. 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 99mTc-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 99mTc-(6-AcBTZ)2DTPA 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 99mTc-metal-based SPECT neurotracer holds potential for neuroreceptor mapping.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structure of 3,6-disubstituted benzothiazolone derivatives reported for (B, C) 5-HT1A, (E) 5-HT6, (B) D2, and (A, C, D) σ1 receptors.
Figure 2
Figure 2
End-to-end distances of four derivatives of the (AcBTZ)2DTPA molecule.
Figure 3
Figure 3
DFT-optimized structure of Tc-(6-AcBTZ)2DTPA using (left) Maestro and (right) Mercury tools, wherein Tc-metal occupies an octahedral geometry with DTPA.
Figure 4
Figure 4
Physicochemical characterizations: (a) UV–Vis and (b) potentiometric titration of the (6-AcBTZ)2DTPA ligand.
Scheme 1
Scheme 1. Synthesis of (6-AcBTZ)2DTPA Using the Bivalent Ligand Approach
Figure 5
Figure 5
Biocompatibility, stability, and pharmacokinetics studies: (a) MTT assay and (b) hemolysis study, (c) radiolabeling efficiency in saline, (d) cysteine challenge test, (e) human serum stability test, and (f) blood kinetics evaluation studies.
Figure 6
Figure 6
Dynamic SPECT scan and time–activity curve of 99mTc-(6-AcBTZ)2DTPA.
Figure 7
Figure 7
Biodistribution studies of 99mTc-(6-AcBTZ)2DTPA.
Figure 8
Figure 8
(a) Regional localization and (b) selectivity studies of 99mTc-(6-AcBTZ)2DTPA.
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