Impact of Novel Antidepressants on Cardiac ¹²³I-Metaiodobenzylguanidine Uptake: Experimental Studies on SK-N-SH Cells and Healthy Rabbits

Abstract

123 I-metaiodobenzylguanidine ( 123 I-MIBG) has independent prognostic value for risk stratification among heart failure patients, but the use of concomitant medication should not affect its quantitative information. We evaluated whether the 4 classes of antidepressants currently most prescribed as first-line treatment for major depressive disorder (MDD) have the potential to alter 123 I-MIBG imaging results. Methods: The inhibition effect of desipramine, escitalopram, venlafaxine, and bupropion on 131 I-MIBG uptake was assessed by in vitro uptake assays using human neuroblastoma SK-N-SH cells. The half-maximal inhibitory concentration of tracer uptake was determined from dose-response curves. To evaluate the effect of intravenous pretreatment with desipramine (1.5 mg/kg) and escitalopram (2.5 or 15 mg/kg) on 123 I-MIBG cardiac uptake, in vivo planar 123 I-MIBG scanning of healthy New Zealand White rabbits was performed. Results: The half-maximal inhibitory concentrations of desipramine, escitalopram, venlafaxine, and bupropion on 131 I-MIBG cellular uptake were 11.9 nM, 7.5 μM, 4.92 μM, and 12.9 μM, respectively. At the maximum serum concentration (as derived by previous clinical trials), the inhibition rates of 131 I-MIBG uptake were 90.6% for desipramine, 25.5% for venlafaxine, 11.7% for bupropion, and 0.72% for escitalopram. A low inhibition rate for escitalopram in the cell uptake study triggered investigation of an in vivo rabbit model: with a dosage considerably higher than used in clinical practice, the noninhibitory effect of escitalopram was confirmed. Furthermore, pretreatment with desipramine markedly reduced cardiac 123 I-MIBG uptake. Conclusion: In the present in vitro binding assay and in vivo rabbit study, the selective serotonin reuptake inhibitor escitalopram had no major impact on neuronal cardiac 123 I-MIBG uptake within therapeutic dose ranges, whereas other types of first-line antidepressants for MDD treatment led to a significant decrease. These preliminary results warrant further confirmatory clinical trials regarding the reliability of cardiac 123 I-MIBG imaging, in particular, if the patient's neuropsychiatric status would not tolerate withdrawal of a potentially norepinephrine-interfering antidepressant.

PARP-1–Targeted Auger Emitters Display High-LET Cytotoxic Properties In Vitro but Show Limited Therapeutic Utility in Solid Tumor Models of Human Neuroblastoma

“…1). 125 I-MIBG uptake was measured after a 2-h incubation at the nonsaturating concentrations used in the cytotoxicity assay (#925 kBq/mL) with or without blocking with 10 mM of desipramine (12).…”

Selective serotonin reuptake inhibitors (SSRIs) prevent meta-iodobenzylguanidine (MIBG) uptake in platelets without affecting neuroblastoma tumor uptake

“…Presumably, this suppression results in more "leftover capacity" for NET to transport MIBG intracellular in the sympathetic end organs. In contrast, a recent in vivo rabbit study found no impact of the SSRI escitalopram on cardiac [ 123 I]MIBG uptake [36]. In the liver, citalopram and paroxetine had diametrically opposed effects on the MIBG accumulation.…”

SPECT vs. PET in cardiac innervation imaging: clash of the titans

“…These findings were further corroborated by electric field stimulation in isolated perfused rabbit hearts: this approach lead to increased washout rate of 18 F-LMI1195, as it provoques vesicular NE release [ 46 ]. Of note, all of those studies were conducted using rabbit myocardium: similar to the human heart, the contribution of NE clearance to neuronal uptake-1 is also pronounced in rabbits and, therefore, the rabbit heart serves as a suitable platform to mimic human cardiac nerve status [ 48 , 49 ]. However, our research group also recently investigated (vesicle-poor) SK-N-SH cells vs. (vesicle-rich) PC12 cells in combination with 18 F-LMI1195 and we found that stimulants for storage vesicle turnover (reserpine, high potassium chloride) enhanced 18 F-LMI1195 washout from PC12 cells, while radiotracer retention remained stable in SK-N-SH cells [ 50 ].…”