Design, physico-chemical and pre-clinical evaluation of a homo-bivalent 99mTc-(BTZ)2DTPA radioligand for targeting dimeric 5-HT1A/5-HT7 receptors
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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DOI：
10.1039/c8nj00089a
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发表时间：
2018-09
影响因子：
3.3
通讯作者：
Preeti Jha;S. Chaturvedi;A. Kaul;Pradeep Pant;Anju;S. Pal;N. Jain;A. Mishra
中科院分区：
文献类型：
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作者：
Preeti Jha;S. Chaturvedi;A. Kaul;Pradeep Pant;Anju;S. Pal;N. Jain;A. Mishra
采用“二价配体方法”设计了一种混合亲和二聚体放射性配体99 mTc-（BTZ）2DTPA，并评价了其作为靶向中枢神经系统5-HT 1A/5-HT 7二聚体受体的SPECT显像剂。计算机模拟研究反映了对二聚体5-HT 1A/5-HT 7受体的高亲和力。经过多步合成，以87.5%的产率获得配体。详细的物理化学分析包括pKa评价和放射性标记参数的优化（>98%放射性标记效率）。99 mTc-复合物的体外血清稳定性试验显示，当用过量半胱氨酸（≤4.4%解离）挑战时，解离率≤8.7%，具有明显的稳定性。细胞相容性（100 μM至1 pM时4.8-0.6%细胞死亡）和血液相容性（1.05%红细胞破坏）表明生物相容性最佳。血液动力学显示双相清除。0.66的脑/血比保证了所开发的放射性配体的CNS渗透能力和BBB渗透性。生物分布和体内SPECT成像显示，在注射后10分钟，最大脑摄取为2.08 ± 0.08% ID/g。随后在5-HT 1A/5-HT 7受体富集区即，小鼠脑海马（41.83%ID/g）和皮层（23.56%ID/g），确定了99 mTc-（BTZ）2DTPA的选择性靶向性。放射性示踪剂主要通过肾脏途径排泄。这些临床前研究表明，99 mTc-（BTZ）2DTPA放射性示踪剂显示出作为神经系统疾病的有效诊断剂的前景。
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.