Purpose <p>^203/212Pb is a promising theranostic isotope pair for targeted alpha therapy (TAT) of neuroendocrine tumors (NET). VMT-α-NET is a novel SSTR2 targeting peptide that can be labeled with both isotopes. The aim of this work was to perform first clinical investigations of [^203/212Pb]Pb-VMT-α-NET regarding imaging, biokinetics, tolerability and response.</p> Methods <p>12 patients (9 m/3 w; mean age 71, range 60–84) with progressive metastatic GEP-NET grade 1–3 received diagnostic imaging with [²⁰³Pb]Pb-VMT-α-NET (4.9 MBq/kg bw) up to 24 h p.i. (whole body &amp; SPECT/CT) and, if eligible, a single dose of [²¹²Pb]Pb-VMT-α-NET therapy (1.2 MBq/kg bw) after exhaustion of all current therapies (including [¹⁷⁷Lu]Lu- &amp; [²²⁵Ac]Ac-DOTATATE), and post-treatment imaging with [²¹²Pb]Pb-VMT-α-NET up to 24 h p.i. (whole body &amp; SPECT/CT). Clinical and laboratory parameters were monitored. A visual and quantitative comparison was made with [⁶⁸&#xa0;Ga]Ga-DOTATATE PET scans before and 3&#xa0;months after therapy.</p> Results <p>No high-grade adverse effects were observed in all patients evaluated with [²⁰³Pb]Pb-VMT-α-NET. All patients showed an initial high, but lesion-dependent heterogeneous intratumoral accumulation, comparable to [⁶⁸&#xa0;Ga]Ga-DOTATATE PET. Treatment with [²¹²Pb]Pb-VMT-α-NET was also well tolerated by all patients without high-grade or serious adverse side effects. Post-therapeutic PET scans and tumor marker controls showed stable findings in all patients up to 3&#xa0;months after treatment.</p> Conclusion <p>Imaging with [²⁰³Pb]Pb-VMT-α-NET followed by a single dose of [²¹²Pb]Pb-VMT-α-NET appears to be well tolerated with promising efficacy, even in a heterogenous and heavily pretreated patient population. Further studies are warranted to examine tolerability and efficacy over multiple treatment cycles in larger patient populations.</p>