Side-by-Side Comparison of the In Vivo Performance of [²¹²Pb]Pb-DOTAMTATE and Other SSTR2-Targeting Compounds

There are numerous versions of octreotide and octreotate, including DOTAMTATE, DOTATATE, JR11, and lead-specific chelator (PSC)-PEG2-TOC. These peptides, which can be either analogs or antagonists, are used in nuclear medicine for diagnostic imaging or targeted radionuclide therapy of neuroendocrine tumors that are positive for somatostatin receptors (SSTRs). Despite their structural and targeting similarities, they have distinct properties and clinical uses. We aimed to perform an extensive preclinical comparison of all these somatostatin analogs with ²¹²Pb, directly studying their pharmacokinetic properties in tumors overexpressing SSTR2. Methods: All SSTR2 analogs were manufactured with the DOTAM, PSC, or DOTA chelators for appropriate comparison after radiolabeling with ²¹²Pb. Chelation, quantification, and pharmacokinetics were compared side by side in AR42J-tumor-bearing animals. Results: These findings highlight the superior chelation efficiency and faster kinetics of DOTAM and then DOTA compared with the PSC. We also discovered a superior tumor-to-kidney area under the curve ratio for [²¹²Pb]Pb-DOTAMTATE over other SSTR2-targeting peptides when radiolabeled with ²¹²Pb. Conclusion: Taken together, the results indicates that [²¹²Pb]Pb-DOTAMTATE has favorable tumor retention and a more favorable dosimetry profile, which is crucial for targeted α-therapy in treating SSTR2-positive neuroendocrine tumors.