Discrepant uptake of the radiolabeled norepinephrine analogues hydroxyephedrine (HED) and metaiodobenzylguanidine (MIBG) in rat hearts

Rischpler, Christoph; Fukui, Kenji; Isoda, Takuro; Javadi, Mehrbod S.; Dannals, Robert F.; Abraham, Roselle; Wahl, Richard L.; Bengel, Frank M.; Higuchi, Takahiro

doi:10.1007/s00259-013-2393-z

Cited by 22 publications

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“…Therefore, 18 F-LMI1195 transport via the extraneural uptake-2 mechanism was suggested and is consistent with transport considerably mediated by uptake-2 in the small rodent hearts. On the other hand, 11 Chydroxyephedrine demonstrated sensitivity for the desipramine treatment even in the in vivo rat heart, whereas 123 I-MIBG uptake was not affected in the same way as 18 F-LMI1195 uptake (19). Consistent with these findings, DeGrado et al also demonstrated the high affinity of 11 C-hydroxyephedrine to uptake-1 using isolated perfused rat hearts (20).…”

Section: Discussionsupporting

confidence: 77%

Retention Kinetics of the ¹⁸F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with ¹¹C-Hydroxyephedrine and ¹²³I-MIBG

et al. 2015

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]-guanidine (18 F-LMI1195) is a new PET tracer designed for noninvasive assessment of sympathetic innervation of the heart. The 18 F label facilitates the imaging advantages of PET over SPECT technology while allowing centralized manufacturing. Highly specific neural uptake of 18 F-LMI1195 has previously been established, but the retention kinetics are not yet fully understood. Methods: Healthy New Zealand White rabbits were studied with 18 F-LMI1195 using a small-animal PET system. Dynamic 40-min chest scans were started just before intravenous bolus injection of 18 F-LMI1195. Imaging was performed under norepineph-rine transport inhibition with desipramine pretreatment, a 1.5 mg/kg desipramine chase administered 10 min after tracer injection, and saline treatment of controls. As a reference, cardiac uptake of 11 C-hydroxyephedrine and 123 I-metaiodobenzylguanidine (123 I-MIBG) was examined by PET and planar scintigraphy, respectively. Results: Cardiac uptake of all 3 tracers was inhibited by pretreatment with desipramine. Stable cardiac tracer retention was delineated by dynamic PET in control rabbits for 11 C-hydroxyephedrine (washout rate, 0.42% ± 0.57%/min) and 18 F-LMI1195 (washout rate, 0.058% ± 0.28%/min). A desipramine chase increased 11 C-hydroxyephedrine washout from the heart (2.43% ± 0.15%/min, P , 0.001), whereas 18 F-LMI1195 washout was not influenced (0.059% ± 0.11%/min, not statistically significant). Additionally, a desipramine chase did not change the cardiac 123 I-MIBG uptake (delayed heart-to-mediastinum ratio, 1.99 ± 0.12 (desipramine chase) vs. 2.05 ± 0.16 (controls), not statistically significant). Conclusion: In vivo norepinephrine transporter (NET) blockade with desipramine confirmed specific neural uptake of 18 F-LMI1195, 11 C-hydroxyephedrine, and 123 I-MIBG in rabbit hearts. 11 C-hydroxyephedrine cardiac retention was sensitive to a NET inhibitor chase, indicating a cycle of continuous NET uptake and release at the nerve terminals. In contrast, 18 F-LMI1195 and 123 I-MIBG demonstrated stable storage at the nerve terminal with resistance to a NET inhibitor chase, mimicking physiologic norepinephrine turnover.

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Section: Discussionsupporting

confidence: 77%

Retention Kinetics of the ¹⁸F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with ¹¹C-Hydroxyephedrine and ¹²³I-MIBG

et al. 2015

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“…The precise complex structure and molecular mechanism of inhibition of the norepinephrine transporter, the molecule responsible for neural uptake-1, by desipramine has been identified recently (27). The successful reduction in uptake of the cardiac 11 Clabeled PET tracer 11 C-hydroxyephedrine in rat hearts using the same blockage protocol (a 2 mg/kg dose of desipramine 10 min before tracer administration) has been reported (28). On the other hand, cardiac uptake of the SPECT tracer 123 I-metaiodobenzylguanidine was preserved in the same way as 18 F-LMI1195 in the present data (28).…”

Section: Discussionmentioning

confidence: 92%

“…The successful reduction in uptake of the cardiac 11 Clabeled PET tracer 11 C-hydroxyephedrine in rat hearts using the same blockage protocol (a 2 mg/kg dose of desipramine 10 min before tracer administration) has been reported (28). On the other hand, cardiac uptake of the SPECT tracer 123 I-metaiodobenzylguanidine was preserved in the same way as 18 F-LMI1195 in the present data (28). 18 F-LMI1195 and 123 I-metaiodobenzylguanidine share a benzylguanidine-analog structure, possibly explaining the similarity of response to the blocker.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the ¹⁸F-Labeled PET Tracer LMI1195 for Imaging Norepinephrine Handling in Rat Hearts

et al. 2013

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A novel 18 F-labeled tracer, LMI1195 (N-[3-bromo-4-(3-18 F-fluoropropoxy)-benzyl]-guanidine), is being developed for sympathetic nerve imaging; its high specificity for neural uptake-1 mechanism has previously been demonstrated in cell associative studies and in rabbit and nonhuman primate studies assessing heart uptake. The aim of this study was to investigate the mechanisms of 18 F-LMI1195 cardiac uptake in the rat, which is known to contain norepinephrine uptake mechanisms beyond uptake-1. Methods: Tracer accumulation in the heart was studied over time after intravenous administration of 18 F-LMI1195 in healthy male Wistar rats by quantitative in vivo PET imaging. The uptake mechanism was assessed by pretreatment with the nonselective norepinephrine uptake-1 and norepinephrine uptake-2 inhibitor phenoxybenzamine (50 mg/kg intravenously; n 5 4), the selective norepinephrine uptake-1 inhibitor desipramine (2 mg/kg intravenously; n 5 4), or saline control (intravenously; n 5 4). Results: 18 F-LMI1195 produced high and sustained heart uptake allowing clear delineation of the left ventricular wall over 60 min after tracer administration. Pretreatment with phenoxybenzamine markedly reduced the 18 F-LMI1195 cardiac uptake when compared with controls. In contrast, there was preserved 18 F-LMI1195 uptake after desipramine pretreatment. Conclusion: In rats, cardiac uptake of 18 F-LMI1195 was significantly inhibited by phenoxybenzamine but not desipramine, suggesting 18 F-LMI1195 is a substrate for the uptake-2 mechanism and is consistent with the rat heart having a dominant level of the mechanism.

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“…However, recent data show that desipramine is unable to significantly inhibit cardiac uptake of 18 F-LMI1195 (18) or its analog MIBG (19) in rats. Our results are in agreement with these latest findings.…”

Section: Discussionmentioning

confidence: 98%

Preclinical Evaluation of ¹⁸F-LMI1195 for In Vivo Imaging of Pheochromocytoma in the MENX Tumor Model

et al. 2013

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We evaluated 18 F-LMI1195 (1-(3-bromo-4-(3-18 F-fluoro-propoxy)benzyl) guanidine), a metaiodobenzylguanidine (MIBG) analog, for the detection of pheochromocytoma in a preclinical in vivo model of endogenous neuroendocrine tumors (multiple endocrine neoplasia [MENX]). Methods: Adrenal uptake kinetics of 18 F-LMI1195 were evaluated in healthy Wistar rats (n 5 6) by dynamic PET imaging. Distribution of 18 F-LMI1195 was evaluated in tumor-bearing MENX mut/mut rats (n 5 10) and control MENX wild-type rats (n 5 4) by biodistribution studies and PET imaging. Biodistribution of 18 F-LMI1195 was compared with 123 I-MIBG in MENX mut/mut rats (n 5 6) and correlated with histological tumor volume and norepinephrine transporter (NET) expression. Uptake specificity was evaluated by in vivo inhibition of the NET by desipramine (n 5 6). Intraadrenal distribution of 18 F-LMI1195 was evaluated by autoradiography. Results: 18 F-LMI1195 showed rapid tracer accumulation in adrenal glands 1 min after tracer injection. Adrenal glands of MENX mut/mut animals showed significantly higher standardized uptake value than MENX wild-type controls (maximum SUV, 10.3 6 2.3 vs. 6.1 6 0.9, P , 0.01). Adrenal uptake in MENX mut/mut rats could be inhibited by desipramine, shown by biodistribution studies (0.06 6 0.01 vs. 0.16 6 0.05 percentage injected dose, P , 0.01), PET imaging (maximum SUV, 3.8 6 0.8 vs. 10.3 6 2.3, P , 0.01), and autoradiography. Adrenal uptake of 18 F-LMI1195 correlated with 123 I-MIBG uptake (r 5 0.91), histological tumor volume (r 5 0.68), and NET expression (r 5 0.50). 18 F-LMI1195 showed an overall favorable distribution for tumor imaging. Conclusion: 18 F-LMI1195 shows high and specific accumulation in pheochromocytomas. Its favorable biodistribution makes it a promising PET tracer for tumor imaging. Further studies are warranted to evaluate its clinical value in oncologic indications.

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Discrepant uptake of the radiolabeled norepinephrine analogues hydroxyephedrine (HED) and metaiodobenzylguanidine (MIBG) in rat hearts

Abstract: HED uptake showed high specificity to neural uptake-1 in rat hearts. On the other hand, (123)I/(131)I-MIBG demonstrated distinct characters of regional tracer distribution and uptake mechanism that are compatible with significant contribution of nonneural uptake-2.

Cited by 22 publications

References 20 publications

Retention Kinetics of the ¹⁸F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with ¹¹C-Hydroxyephedrine and ¹²³I-MIBG

Retention Kinetics of the ¹⁸F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with ¹¹C-Hydroxyephedrine and ¹²³I-MIBG

Assessment of the ¹⁸F-Labeled PET Tracer LMI1195 for Imaging Norepinephrine Handling in Rat Hearts

Preclinical Evaluation of ¹⁸F-LMI1195 for In Vivo Imaging of Pheochromocytoma in the MENX Tumor Model

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Discrepant uptake of the radiolabeled norepinephrine analogues hydroxyephedrine (HED) and metaiodobenzylguanidine (MIBG) in rat hearts

Abstract: HED uptake showed high specificity to neural uptake-1 in rat hearts. On the other hand, (123)I/(131)I-MIBG demonstrated distinct characters of regional tracer distribution and uptake mechanism that are compatible with significant contribution of nonneural uptake-2.

Cited by 22 publications

References 20 publications

Retention Kinetics of the 18F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with 11C-Hydroxyephedrine and 123I-MIBG

Retention Kinetics of the 18F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with 11C-Hydroxyephedrine and 123I-MIBG

Assessment of the 18F-Labeled PET Tracer LMI1195 for Imaging Norepinephrine Handling in Rat Hearts

Preclinical Evaluation of 18F-LMI1195 for In Vivo Imaging of Pheochromocytoma in the MENX Tumor Model

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Retention Kinetics of the ¹⁸F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with ¹¹C-Hydroxyephedrine and ¹²³I-MIBG

Retention Kinetics of the ¹⁸F-Labeled Sympathetic Nerve PET Tracer LMI1195: Comparison with ¹¹C-Hydroxyephedrine and ¹²³I-MIBG

Assessment of the ¹⁸F-Labeled PET Tracer LMI1195 for Imaging Norepinephrine Handling in Rat Hearts

Preclinical Evaluation of ¹⁸F-LMI1195 for In Vivo Imaging of Pheochromocytoma in the MENX Tumor Model