Purpose: ^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. Methods: 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 & 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- & [²²⁵Ac]Ac-DOTATATE), and post-treatment imaging with [²¹²Pb]Pb-VMT-α-NET up to 24 h p.i. (whole body & SPECT/CT). Clinical and laboratory parameters were monitored. A visual and quantitative comparison was made with [⁶⁸ Ga]Ga-DOTATATE PET scans before and 3 months after therapy. Results: 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 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 months after treatment. Conclusion: 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.

Background: ²⁰³Pb and ²¹²Pb show promise as theragnostic agents for targeted alpha therapy (TAT) because two chemically identical isotopes can be used for diagnostic imaging and treatment. In the ²¹²Pb decay chain, in addition to alpha and beta particles, a large number of photons are emitted, those with an energy of 239 keV and the characteristic X-rays of ²¹²Pb could be used for imaging. ²⁰³Pb decays by photon emission with an energy of 279 keV, which appears suitable for gamma camera imaging. The aim of this study was to investigate suitable imaging protocols and to characterize the scintigraphic imaging properties and their implications for the clinical feasibility as theragnostic isotopes. Methods: Planar and SPECT/CT images were obtained with medium- and high-energy collimators on a Siemens Symbia Intevo 6 using a NEMA image quality phantom in various phantom setups and another body-shaped phantom with several inserts. Different energy windows were investigated and measurements were evaluated in terms of sensitivity, count rate performance, spatial resolution, contrast recovery, lesion detectability, and image quantification. Results: Evaluation of image quality showed superior imaging characteristics for ²⁰³Pb compared to ²¹²Pb regarding spatial resolution, contrast recovery, image noise, and quantification accuracy. Both medium- and high- energy collimators were suitable for ²⁰³Pb imaging, with the medium energy collimators showed slightly better imaging properties. Images obtained with the HE collimators in the 79 keV energy window showed the best visual image quality for ²¹²Pb. Due to high-energy photon emissions from ²¹²Pb daughter nuclides (e.g., 2.6 MeV from ²⁰⁸Tl), dead time related count losses occurred even at low activities (20% count loss at 20 MBq for MELP collimators). Conclusions: According to our results and first-in-human imaging studies, SPECT/CT imaging with the ^203/212Pb theragnostic pair is clinically feasible. ²⁰³Pb is an appropriate imaging surrogate to investigate pharmacokinetics and perform predictive dosimetry. The less favorable imaging characteristics of ²¹²Pb make image quantification and post-treatment dosimetry challenging and require further research.

Background: The administration of a ¹⁶⁶Ho scout dose is available as an alternative to ^99mTc particles for pre-treatment imaging in Selective Internal Radiation Therapy (SIRT). It has been reported that the ¹⁶⁶Ho scout dose may be more accurate for the prediction of microsphere distribution and the associated therapy planning. The aim of the current study is to compare the scintigraphic imaging characteristics of both isotopes, considering the objectives of the pre-treatment imaging using clinically geared phantoms. Methods: Planar and SPECT/CT images were obtained using a NEMA image quality phantom in different phantom setups and another body-shaped phantom with several inserts. The influence of collimator type, count statistics, dead time effects, isotope properties and patient obesity on spatial resolution, contrast recovery and the detectability of small activity accumulations was investigated. Furthermore, the effects of the imaging characteristics on personalized dosimetry are discussed. Results: The images with ^99mTc showed up to 3 mm better spatial resolution, up to two times higher contrast recovery and significantly lower image noise than those with ¹⁶⁶Ho. The contrast-to-noise ratio was up to five times higher for ^99mTc than for ¹⁶⁶Ho. Only when using ^99mTc all activity-filled spheres could be distinguished from the activity-filled background. The measurements mimicking an obese patient resulted in a degraded image quality for both isotopes. Conclusions: Our measurements demonstrate better scintigraphic imaging properties for ^99mTc compared to ¹⁶⁶Ho in terms of spatial resolution, contrast recovery, image noise, and lesion detectability. While the ¹⁶⁶Ho scout dose promises better prediction of the microsphere distribution, it is important to consider the inferior imaging characteristics of ¹⁶⁶Ho, which may affect individualized treatment planning in SIRT.