Author + information
- Takahiro Higuchi, MD, PhD∗ (, )
- Behrooz H. Yousefi, PhD,
- Sybille Reder, MT,
- Monika Beschorner, MT,
- Iina Laitinen, PhD,
- Ming Yu, MD,
- Simon Robinson, PhD,
- Hans Jürgen Wester, PhD,
- Markus Schwaiger, MD and
- Stephan G. Nekolla, PhD
- ↵∗Department of Nuclear Medicine, University of Würzburg, Oberdürrbacher Strasse 6, D-97080 Würzburg, Germany
A radionuclide tracer approach is a unique assay to monitor the cardiac sympathetic nervous system in patients, and the most widely available tracer is the radiolabeled norepinephrine analogue [123I]-metaiodobenzylguanidine ([123I]-MIBG). A novel 18F-labeled positron emission tomography (PET) tracer, [18F]-LMI1195 (N-[3-bromo-4-(3-[18F]fluoro-propoxy)-benzyl]-guanidine), has been developed to overcome the limitations of conventional tracers (1). [18F]-LMI1195 shares similarities with [123I]-MIBG based on its benzylguanidine structure, but higher sensitivity and specificity and more accurate quantification are expected via the general advantages of PET over single-photon emission computed tomography technology. The high specificity of [18F]-LMI1195 for the norepinephrine transporter was confirmed with a cell-binding assay and in vivo imaging (1,2). Most recently, a human volunteer study demonstrated promising results with uniform tracer uptake in the ventricular wall and acceptable radiation doses (3).
We aimed to evaluate further tracer kinetics at the nerve terminal. First-pass tracer extraction fraction (EF) and washout were measured in isolated rabbit hearts (New Zealand White) to avoid systemic recirculation and metabolism of the tracer.
The EF was determined at different flow values (n = 19). Additionally, the influence of desipramine hydrochloride (40 nM) added into the buffer (n = 5) and reserpine–pre-treated hearts (n = 5) were tested. Reserpine pre-treatment was performed with intravenous injection of reserpine (2 mg/kg) 3 h before the study.
A second protocol was designed to measure tracer washout. Hearts were perfused with [18F]-LMI1195 added to the buffer for 10 min (incubation phase) followed by 25 min of perfusion without tracer (washout phase). The tracer washout was examined by control Krebs-Henseleit bicarbonate buffer (n = 9), and desipramine was added (desipramine-chase; n = 5), with washout with electrical field stimulation (5 Hz, 5 V, 1 min × 5 times at the washout phase; n = 7).
There was a flow-dependent decrease in the EF, with 44.4 ± 5.1%, 28.1 ± 6.5%, and 21.5 ± 5.1% using flow values of 2, 4, and 8 ml/min/g, respectively. Desipramine, a specific neural uptake-1 blocker, decreased the EF significantly from 28.1 ± 6.5% (control) to 4.3 ± 3.8% (p < 0.001). Reserpine, an irreversible vesicular monoamine transporter blocker, pre-treatment did not change the EF (30.1 ± 3.4%; p = NS) (Figure 1).
There was tracer washout with 0.73 ± 0.18 %/min in the first 20-min measurement. Desipramine added only during washout phase did not change the washout rate (0.94 ± 0.12 %/min). On the other hand, electrical field stimulation to enhance the vesicular release of norepinephrine increased the washout rate significantly (1.96 ± 0.48 %/min; p < 0.01).
In summary, we measured the myocardial kinetics of [18F]-LMI1195 with isolated perfused rabbit hearts. Specific uptake at the nerve terminal was confirmed by desipramine sensitive uptake. Furthermore, we observed enhanced tracer washout with electrical stimulation, as well as resistance for desipramine chase, suggesting that the tracer handling in the nerve terminals was consistent with norepinephrine vesicular storage and release.
The mechanistic insights of [18F]-LMI1195 uptake assessed in an isolated heart model might be relevant in the design of clinical imaging protocols, as well as the interpretation of imaging results in patients. However, further complementary in vivo animal experiments are needed to confirm and extended these findings for clinical studies.
Please note: Drs. Yu and Robinson are employees of Lantheus Medical Imaging. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Higuchi and Yousefi contributed equally to this work.
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