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Issue 18, 2018
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Design, physico-chemical and pre-clinical evaluation of a homo-bivalent 99mTc-(BTZ)2DTPA radioligand for targeting dimeric 5-HT1A/5-HT7 receptors

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Abstract

A mixed affinity dimeric radioligand 99mTc-(BTZ)2DTPA was designed using a “bivalent ligand approach” and evaluated as an SPECT imaging agent for targeting 5-HT1A/5-HT7 dimeric receptors in the central nervous system. In silico studies reflected high affinity for dimeric 5-HT1A/5-HT7 receptors. Following multi-step synthesis, the ligand was obtained in 87.5% yield. Detailed physico-chemical analysis included pKa evaluation and optimization of radiolabeling parameters (>98% radiolabeling efficiency). The in vitro serum-stability test of the 99mTc-complex showed ≤8.7% dissociation and appreciable stability when challenged with excess cysteine (≤4.4% dissociation). Cyto-compatibility (4.8–0.6% cell death at 100 μM to 1 pM) and haemo-compatibility (1.05% erythrocyte destruction) suggested optimum biocompatibility. Blood kinetics revealed biphasic clearance. The brain/blood ratio of 0.66 assured the CNS penetration ability and BBB permeability of the developed radioligand. Bio-distribution and in vivo SPECT imaging revealed a maximum brain uptake of 2.08 ± 0.08% ID per g at 10 min p.i. followed by major activity accumulation in 5-HT1A/5-HT7 receptor-rich regions viz., the hippocampus (41.83% ID per g) and the cortex (23.56% ID per g) of mouse brains ascertaining selective targeting of 99mTc-(BTZ)2DTPA. The radiotracer was excreted majorly through the renal route. These preclinical studies reveal that the 99mTc-(BTZ)2DTPA radiotracer shows promise as an effective diagnostic agent for neurological disorders.

Graphical abstract: Design, physico-chemical and pre-clinical evaluation of a homo-bivalent 99mTc-(BTZ)2DTPA radioligand for targeting dimeric 5-HT1A/5-HT7 receptors

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Supplementary files

Article information


Submitted
07 Jan 2018
Accepted
20 Jul 2018
First published
16 Aug 2018

New J. Chem., 2018,42, 15032-15043
Article type
Paper

Design, physico-chemical and pre-clinical evaluation of a homo-bivalent 99mTc-(BTZ)2DTPA radioligand for targeting dimeric 5-HT1A/5-HT7 receptors

P. Jha, S. Chaturvedi, A. Kaul, P. Pant, Anju, S. Pal, N. Jain and A. K. Mishra, New J. Chem., 2018, 42, 15032
DOI: 10.1039/C8NJ00089A

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