Development of 203Pb-labeled SSTR2 radioligands for neuroendocrine tumors (NETs) imaging

Dylan Chapeau, Sofia Koustoulidou, Erik de Blois, Mark Konijnenberg, Marion De Jong, Yann Seimbille

Research output: Contribution to journalMeeting AbstractAcademicpeer-review


Objectives: Development of theranostic pairs is generally guided by the biodistribution and pharmacokinetic properties of the imaging agent. Indeed, conducting such studies with beta or alpha emitters, such as lead-212, can be challenging. Therefore, it is often preferable to use a surrogate to facilitate detection of radioactivity
in tissues, follow distribution of the radioactive drug over time by non-invasive imaging, and ease radiation safety. In this context, lead203, a gamma emitter (t1/2 =52 h), is perfectly adapted to study the distribution of 212Pb-labeled drugs, as it provides chemically identical companion diagnostics. Our objective was therefore to design and pre-clinically evaluate two novel 203Pb-labeled SSTR2 ligands for theranostic application of NETs.

Methods: Two octreotate derivatives, containing a 4-(aminomethyl)cyclohexane-1-carbonyl (Amcha) or a 4-amino-1-carboxymethyl-piperidinyl (Pip) linker, were synthesized by SPPS. In vitro competitive binding assays with [111In]In-DOTATATE were performed using CHO-K1 cell membranes over-expressing human SSTR2. Both ligands were labeled with 203Pb in sodium acetate buffer for 20 minutes at room temperature and analyzed by iTLC and radioHPLC. LogD7.4 and stability in serum were also determined. SPECT/CT imaging was performed at 1, 4 and 24 h post-injection in H69 tumorbearing mice, followed by ex-vivo biodistribution.

Results: DO3AM-Amcha-TATE and DO3AM-Pip-TATE were successfully synthesized with a yield and purity of 10% and 99%, respectively. Both ligands showed low nanomolar binding affinity for SSTR2 and hydrophilic behavior. DO3AM-Amcha-TATE and DO3AM-PipTATE were labeled with 203Pb with a radiochemical yield and purity exceeding 98%. Stability studies revealed that our 203Pb-labeled octreotate derivatives were stable in serum for 24 h. Image analysis of the two radioligands showed high uptake at 1 h in the SSTR2-positive
tumors (4.0 ± 0.57 and 3.3 ± 1.08%ID/mL for [203Pb]Pb-DO3AMAmcha-TATE and [203Pb]Pb-DO3AM-PIP-TATE, respectively), as well as in the kidneys ([203Pb]Pb-DO3AM-Amcha-TATE: 10.6 ± 1.7%ID/mL and [203Pb]Pb-DO3AM-Pip-TATE: 12.8 ± 1.80%ID/mL), but also at 24 h p.i. (tumors: 2.4 ± 0.27%ID/mL and 2.2 ± 0.64%ID/mL; kidneys: 3.6 ± 1.2%ID/mL and 6.6 ± 1.17%ID/mL for [203Pb]Pb-DO3AM-Amcha-TATE and [203Pb]Pb-DO3AM-Pip-TATE, respectively). The tumor-to-kidney ratio increased over time for [203Pb]Pb-DO3AM-Amcha-TATE (0.4
at 1 h to 0.7 at 24 h p.i.), while it remained constant for the [203Pb] Pb-DO3AM-Pip-TATE (0.26 at 1 h to 0.34 at 24 h p.i.). Ex-vivo biodistribution confirmed that administration of [203Pb]Pb-DO3AMPip-TATE resulted in a higher uptake in the pancreas and bones than [203Pb]Pb-DO3AM-Amcha-TATE.

Conclusions: Our results indicated that these two ligands are promising candidates for imaging of SSTR2-positive tumors. Further investigations will be conducted with the 212Pb-labeled analogs to determine their potential as theranostic agents.
Original languageEnglish
Pages (from-to)S54-S55
Number of pages2
JournalNuclear Medicine and Biology
Publication statusPublished - 2022

Bibliographical note

We are thankful to Kansen voor West (FIELDLAB: Advancing Nuclear Medicine) for the financial support.


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