Background <p>Cardiac sympathetic nerve imaging is critical for sudden death risk stratification in heart failure patients. Conventional SPECT probe [¹²³I]MIBG is limited by inadequate spatial resolution and restricted quantitative ability. While [¹⁸F]-labeled PET probes have shown promise, some suffer from high hepatic uptake that interferes with cardiac signals, and low radiolabeling efficiency hinders clinical translation. Thus, a novel norepinephrine transporter (NET) probe [¹⁸F]MFPBG was developed for cardiac sympathetic nerve imaging, synthesized via an automated radiolabeling module.</p> Results <p>The decay-corrected radiochemical yield of [¹⁸F]MFPBG was 15.14±2.57% (n = 5), with a retention time of 11.87 minutes. The probe exhibited a radiochemical purity of &gt;95% and remained stable (purity &gt;95%) for 4 hours at ambient temperature. The biodistribution studies in ICR mice (n=28) showed a cardiac uptake of 9.34±0.73 %ID/g at 5 minutes post-injection, with the heart to liver ratio (3.99±0.15). At 120 minutes, cardiac uptake remained high (4.88±0.85 %ID/g), and the heart to liver ratio was 4.46±0.85. In Bama miniature pigs, imipramine pre-treatment significantly reduced cardiac uptake compared to controls at 10 minutes (SUV-bw: 2.08±0.16 vs. 3.73±0.29; P &lt; 0.001) and 60 minutes (SUV-bw: 1.21±0.14 vs. 2.15±0.21; P &lt; 0.001).</p> Conclusions <p>[¹⁸F]MFPBG demonstrates NET-mediated uptake, stable cardiac retention, low background noise, and suitability for automated radiolabeling, establishing it as a promising agent for cardiac sympathetic nerve imaging with favorable characteristics that warrant further preclinical validation, including in vivo metabolic profiling, to fully assess its clinical translatability.</p> Graphical abstract <p></p>