Cardiac retention of PET neuronal imaging agent LMI1195 in different species: Impact of norepinephrine uptake-1 and -2 transporters

Yu, Ming; Bozek, J; Kagan, Mikhail; Guaraldi, Mary; Silva, Paula; Azure, Michael; Onthank, David; Robinson, Simon P.

doi:10.1016/j.nucmedbio.2013.03.003

Cited by 20 publications

(15 citation statements)

References 21 publications

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“…uptake-2) in the rat heart. A consistent result could be obtained from denervated rabbits and nonhuman primates (NHP), for the reason that in both animals only uptake 1 is responsible for the NET tracer uptake (Yu et al 2013). Further assessment in rats using the non-selective uptake blocker phenoxybenzamine (PhB) confirmed the existence of both uptake 1 and 2 in rat hearts, where the cardiac uptake of 18 F-LMI1195 could only be reduced by PhB, rather than DMI or saline control .…”

Section: F-lmi1195supporting

confidence: 56%

Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements

et al. 2020

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The norepinephrine transporter (NET) is a major target for the evaluation of the cardiac sympathetic nerve system in patients with heart failure and Parkinson's disease. It is also used in the therapeutic applications against certain types of neuroendocrine tumors, as exemplified by the clinically used 123/131 I-MIBG as theranostic single-photon emission computed tomography (SPECT) agent. With the development of more advanced positron emission tomography (PET) technology, more radiotracers targeting NET have been reported, with superior temporal and spatial resolutions, along with the possibility of functional and kinetic analysis. More recently, fluorine-18-labelled NET tracers have drawn increasing attentions from researchers, due to their longer radiological half-life relative to carbon-11 (110 min vs. 20 min), reduced dependence on on-site cyclotrons, and flexibility in the design of novel tracer structures. In the heart, certain NET tracers provide integral diagnostic information on sympathetic innervation and the nerve status. In the central nervous system, such radiotracers can reveal NET distribution and density in pathological conditions. Most radiotracers targeting cardiac NET-function for the cardiac application consistent of derivatives of either norepinephrine or MIBG with its benzylguanidine core structure, e.g. 11 C-HED and 18 F-LMI1195. In contrast, all NET tracers used in central nervous system applications are derived from clinically used antidepressants. Lastly, possible applications of NET as selective tracers over organic cation transporters (OCTs) in the kidneys and other organs controlled by sympathetic nervous system will also be discussed.

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Section: F-lmi1195supporting

confidence: 56%

Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements

et al. 2020

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“…Furthermore, in vivo PET studies have confirmed the high contrast of 18 F-LMI1195 cardiac uptake in rabbits, monkeys, and humans (4,5). Notably, the specific neural transport observed in these species is not the same as seen in small rodents (16,17). Desipramine treatment did not change the cardiac 18 F-LMI1195 uptake in rat hearts, whereas phenoxybenzamine, a potent norepinephrine nonselective NET inhibitor (18), significantly reduced the tracer uptake.…”

Section: Discussionmentioning

confidence: 89%

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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“…Furthermore, the role of the Uptake-1 and Uptake-2 mechanisms is species-dependent. In humans as well as in rabbits and nonhuman primates, cardiac uptake of MIBG is facilitated by Uptake-1, whereas Uptake-1 is absent in the rat heart [43, 44]. Thus, for assessing cardiac sympathetic neuronal function by imaging, an agent that predominantly reflects Uptake-1 is preferred.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

Vaidyanathan

McDougald

Koumarianou

et al. 2015

Nuclear Medicine and Biology

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Introduction Radioiodinated meta-iodobenzylguanidine (MIBG), a norepinephrine transporter (NET) substrate, has been extensively used as an imaging agent to study the pathophysiology of the heart and for the diagnosis and treatment of neuroendocrine tumors. The goal of this study was to develop an 18F-labeled analogue of MIBG that like MIBG itself could be synthesized in a single radiochemical step. Towards this end, we designed 4-fluoropropoxy-3-iodobenzylguanidine (FPOIBG). Methods Standards of FPOIBG and 4-fluoropropoxy-3-bromobenzylguanidine (FPOBBG) as well as their tosylate precursors for labeling with 18F, and a tin precursor for the preparation of radioiodinated FPOIBG were synthesized. Radiolabeled derivatives were synthesized by nucleophilic substitution and electrophilic iododestannylation from the corresponding precursors. Labeled compounds were evaluated for NET transporter recognition in in vitro assays using three NET-expressing cell lines and in biodistribution experiments in normal mice, with all studies performed in a paired-label format. Competitive inhibition of [125I]MIBG uptake by unlabeled benzylguanidine compounds was performed in UVW-NAT cell line to determine IC50 values. Results [18F]FPOIBG was synthesized from the corresponding tosylate precursor in 5.2 ± 0.5% (n = 6) overall radiochemical yields starting with aqueous fluoride in about 105 min. In a paired-label in vitro assay, the uptake of [18F]FPOIBG at 2 h was 10.2 ± 1.5%, 39.6 ± 13.4%, and 13.3 ± 2.5%, in NET-expressing SK-N-SH, UVW-NAT, and SK-N-BE(2c) cells, respectively, while these values for [125I]MIBG were 57.3 ± 8.1%, 82.7 ± 8.9%, and 66.3 ± 3.6%. The specificity of uptake of both tracers was demonstrated by blocking with desipramine. The 125I-labeled congener of FPOIBG gave similar results. On the other hand, [18F]FPOBBG, a compound recently reported in the literature, demonstrated much higher uptake, albeit less than that of co-incubated [125I]MIBG. IC50 values for FPOIBG were higher than that obtained for MIBG and FPOBBG. Unlike the case with [18F]FPOBBG, the heart uptake [18F]FPOIBG in normal mice was significantly lower than that of MIBG. Conclusion Although [18F]FPOIBG does not appear to warrant further consideration as an 18F-labeled MIBG analogue, analogues wherein the iodine in it is replaced with a chlorine, fluorine or hydrogen might be worth pursuing. Advances in knowledge and implications for patient care An 18F-labeled analogue of the well-known radiopharmaceutical MIBG could have significant impact, potentially improving imaging of NET related disease in cardiology and in the imaging of neuroendocrine tumors. Although 18F-labeled analogues of MIBG have been reported including LMI1195, we undertook this work hypothesizing that based on its greater structural similarity to MIBG, FPOIBG might be a better analogue than LMI1195.

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Cardiac retention of PET neuronal imaging agent LMI1195 in different species: Impact of norepinephrine uptake-1 and -2 transporters

Cited by 20 publications

References 21 publications

Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements

Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements

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

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

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Cardiac retention of PET neuronal imaging agent LMI1195 in different species: Impact of norepinephrine uptake-1 and -2 transporters

Cited by 20 publications

References 21 publications

Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements

Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements

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

Synthesis and evaluation of 4-[18F]fluoropropoxy-3-iodobenzylguanidine ([18F]FPOIBG): A novel 18F-labeled analogue of MIBG

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