Synthesis and preliminary evaluation of [11C]-(−)-phenylepnrine as a functional heart neuronal PET agent

Rosario, Renato B. Del; Jung, Y; Caraher, John; Chakraborty, Pulak K.; Wieland, Donald M.

doi:10.1016/0969-8051(96)00057-1

Cited by 29 publications

(18 citation statements)

References 16 publications

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“…After 2-3 d to allow for recovery, 7 animals were repositioned in the scanner using external skin markers and the laser system of the gantry. 11 C-phenylephrine and 11 C-hydroxyephedrine were synthesized at a specific activity of more than 37 GBq (1 Ci)/mmol as previously described (16,17). 11 C-phenylephrine (600-800 MBq) was injected first, followed by dynamic imaging over 40 min (14 frames; 6 · 30, 2 · 60, 2 · 150, 2 · 300, and 2 · 600 s).…”

Section: Animal Model and Study Protocolmentioning

confidence: 99%

Multiparametric Molecular Imaging Provides Mechanistic Insights into Sympathetic Innervation Impairment in the Viable Infarct Border Zone

et al. 2015

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Impaired catecholamine handling in the viable infarct border zone may play an important role in ventricular remodeling and lethal arrhythmia. We sought to get further biologic insights into cardiac sympathetic neuronal pathology after myocardial infarction, using multiple tomographic imaging techniques. Methods: In a porcine model of myocardial infarction (n 5 13), PET and MR imaging were performed after 4-6 wk and integrated with electrophysiologic testing and postmortem histology. Results: PET with the physiologic neurotransmitter 11 C-epinephrine, which is sensitive to metabolic degradation unless it is stored and protected in neuronal vesicles, identified a defect exceeding the perfusion defect (defined by 13 Nammonia; defect size in all animals, 42 ± 12 vs. 35% ± 12% of left ventricle, P , 0.001). In a subgroup of 7 animals, defect of the metabolically resistant catecholamine 11 C-hydroxyephedrine was smaller than epinephrine (41 ± 8 vs. 47% ± 6% of left ventricle, P 5 0.004), whereas defect of a third catecholamine, 11 C-phenylephrine, which is sensitive to metabolic degradation, was similar to epinephrine (48 ± 6 vs. 47% ± 6%, P 5 0.011 vs. perfusion defect). Histology confirmed the presence of nerve fibers in the infarct border zone. Tagged MR imaging identified impaired peak circumferential wall strain and wall thickening in myocardial segments with epinephrine/perfusion mismatch (n 5 6). Confirmatory of prior work, inducible ventricular tachycardia was associated with a larger epinephrine/perfusion mismatch (n 5 11). Conclusion: In the viable infarct border zone, neuronal vesicular catecholamine storage and protection from metabolic degradation are more severely altered than catecholamine uptake. This alteration may reflect an intermediate state between normal innervation and complete denervation in advanced disease.

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Section: Animal Model and Study Protocolmentioning

confidence: 99%

Multiparametric Molecular Imaging Provides Mechanistic Insights into Sympathetic Innervation Impairment in the Viable Infarct Border Zone

et al. 2015

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“…11 C-phenylephrine (PHEN) is another catecholamine analog that, in contrast to HED, is a substrate to monoamine oxidase (MAO) and thus metabolized intraneuronally. It is considered a marker of leakage from intraneuronal storage vesicles and subsequent metabolism (11). 11 C-epinephrine (EPI) is a true catecholamine that, in contrast to HED and PHEN, is efficiently stored in intraneuronal vesicles, where it is protected from metabolic degradation under normal conditions.…”

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confidence: 99%

“…11 C-meta-hydroxyephedrine (HED), a metabolically resistant catecholamine analog, is recognized as a tracer of neuronal transport (10). 11 C-phenylephrine (PHEN) is another catecholamine analog that, in contrast to HED, is a substrate to monoamine oxidase (MAO) and thus metabolized intraneuronally. It is considered a marker of leakage from intraneuronal storage vesicles and subsequent metabolism (11).…”

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confidence: 99%

“…PET allows for the noninvasive assessment of cardiac sympathetic neuronal integrity using several radiolabeled catecholamine analogs (9). 11 C-meta-hydroxyephedrine (HED), a metabolically resistant catecholamine analog, is recognized as a tracer of neuronal transport (10). 11 C-phenylephrine (PHEN) is another catecholamine analog that, in contrast to HED, is a substrate to monoamine oxidase (MAO) and thus metabolized intraneuronally.…”

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confidence: 99%

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In Vivo PET Imaging of Cardiac Presynaptic Sympathoneuronal Mechanisms in the Rat

Tipre

Fox

Holt³

et al. 2008

J Nucl Med

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The sympathetic nervous system of the heart plays a key role in the pathophysiology of various cardiac diseases. Small-animal models are valuable for obtaining further insight into mechanisms of cardiac disease and therapy. To determine the translational potential of cardiac neuronal imaging from rodents to humans, we characterized the rat sympathetic nervous system using 3 radiotracers that reflect different subcellular mechanisms: 11 C-meta-hydroxyephedrine (HED), a tracer of neuronal transport showing stable uptake and no washout in healthy humans; 11 C-phenylephrine (PHEN), a tracer of vesicular leakage and intraneuronal metabolic degradation with initial uptake and subsequent washout in humans; and 11 C-epinephrine (EPI), a tracer of vesicular storage with stable uptake and no washout in humans. Methods: We used a small-animal PET system to study healthy male Wistar rats at baseline, after desipramine (DMI) pretreatment (DMI block), and with DMI injection 15 min after tracer delivery (DMI chase). The rats were kept under general isoflurane anesthesia while dynamic emission scans of the heart were recorded for 60 min after radiotracer injection. A myocardial retention index was determined by normalizing uptake at 40 min to the integral under the arterial input curve. Washout rates were determined by monoexponential fitting of myocardial time-activity curves. Results: At baseline, HED showed high myocardial uptake and sustained retention, EPI showed moderate uptake and significant biphasic washout, and PHEN showed moderate uptake and monoexponential washout. The average (6 SD) left ventricular retention index for HED, PHEN, and EPI was 7.38% 6 0.82%/min, 3.43% 6 0.45%/min, and 4.24% 6 0.59%/min, respectively; the washout rate for HED, PHEN, and EPI was 0.13% 6 0.23%/min, 1.13% 6 0.35%/min, and 0.50% 6 0.24%/min, respectively. The DMI chase resulted in increased washout only for HED. DMI block decreased myocardial uptake of all tracers by less than 90%. Conclusion: Kinetic profiles of HED in the rat myocardium were similar to those of HED in humans, suggesting comparable neuronal transport density. Unlike in humans, however, significant washout of EPI and faster washout of PHEN were encountered, consistent with high intraneuronal metabolic activity, high catecholamine turnover, and reduced vesicular storage. This evidence of increased neuronal activity in rodents has implications for translational studies of cardiac neuronal biology in humans.

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“…[15][16][17] In all cases, specific activity at the end of synthesis was >3500 mCi/µmol, and radiochemical purity was >95%. N-13 ammonia was prepared as previously described.…”

Section: Pet Imagingmentioning

confidence: 99%

Mechanistic Insights into Sympathetic Neuronal Regeneration

Bravo

Lautamäki

Carter

et al. 2015

Circ: Cardiovascular Imaging

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T he sympathetic nervous system plays a key role in maintaining the homeostasis and integrity of the cardiovascular system. It is impaired in the natural course of various cardiovascular diseases, where imbalance contributes to electromechanical instability and progression of heart failure.1-3 Regeneration of impaired innervation, however, may also occur. See Clinical PerspectiveThe transplanted heart is a unique model in this regard. After transplantation, the heart becomes denervated because of surgical disruption of the extracardiac sympathetic nerve fibers at the base of the heart. However, this process is not complete as the intrinsic cardiac network or ganglia of the transplanted heart has the potential to function independently in the absence of central neuronal inputs. 4 Various studies have shown that the intrinsic cardiac nervous system becomes partly reinnervated by extracardiac sympathetic efferent neurons with time after transplantation. [5][6][7][8] This has been associated with improved left ventricular (LV) performance and exercise capacity after heart transplantation 9 and with improved regulation of myocardial perfusion 10 and substrate utilization.11 Studies evaluating the presence, extent, and functional consequences of restored extracardiac sympathetic innervation, however, have typically used only a single tracer to determine catecholamine uptake and washout. This provides only a snapshot of nerve terminal integrity and does Background-Post-transplant reinnervation is a unique model to study sympathetic neuronal regeneration in vivo. The differential role of subcellular mechanisms of catecholamine handling in nerve terminals has not been investigated. Methods and Results-Three different carbon-11-labeled catecholamines were used for positron emission tomography of transport (C-11 m-hydroxyephedrine, HED), vesicular storage (C-11 epinephrine, EPI), and metabolic degradation (C-11 phenylephrine). A 2-day protocol was used, including quantification of myocardial blood flow by N-13 ammonia.Resting myocardial blood flow and EPI, HED and phenylephrine retention were homogeneous in healthy volunteers (n=7). Washout was only observed for phenylephrine (T 1/2 49±6 min). In nonrejecting, otherwise healthy heart transplant recipients (>1 year after surgery, n=10), resting myocardial blood flow was also homogenous. Regional catecholamine uptake of varying degrees was observed in the anterior left ventricular wall and septum. Overall, 24±19% of left ventricle showed HED uptake levels comparable with healthy volunteers, whereas it was only 8±7% for EPI (P=0.004 versus HED). Phenylephrine washout was not different from healthy volunteers in the area with restored EPI and HED retention (T 1/2 41±7 min; P>0.05), but was significantly enhanced in the EPI/HED mismatch area (T 1/2 36±8 min; P=0.008), consistent with inefficient vesicular storage and enhanced metabolic degradation. Conclusions-Regeneration of subcellular components of sympathetic nerve terminal function does not occur simultaneously.In the rein...

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Synthesis and preliminary evaluation of [11C]-(−)-phenylepnrine as a functional heart neuronal PET agent

Cited by 29 publications

References 16 publications

Multiparametric Molecular Imaging Provides Mechanistic Insights into Sympathetic Innervation Impairment in the Viable Infarct Border Zone

Multiparametric Molecular Imaging Provides Mechanistic Insights into Sympathetic Innervation Impairment in the Viable Infarct Border Zone

In Vivo PET Imaging of Cardiac Presynaptic Sympathoneuronal Mechanisms in the Rat

Mechanistic Insights into Sympathetic Neuronal Regeneration

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