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Published on: September 3, 2013
Development of Highly Potent Clinical Candidates for Theranostic Applications against Cholecystokinin-2 Receptor
Alicia Corlett1, Jo-Anne Pinson2,3, Marwa N Rahimi2,3
1Department of Nuclear Medicine, The Royal Melbourne Hospital, Parkville, Victoria, 3000, Australia.
Abstract:
Peptide receptor radionuclide therapy (PRRT) is a promising form of systemic radiation therapy designed to eradicate cancer. Cholecystokinin-2 receptor (CCK2R) is an important molecular target that is highly expressed in a range of cancers. This study describes the synthesis and in vivo characterization of a novel series of 177Lu-labeled peptides ([177Lu]Lu-2b-4b) in comparison with the reference CCK2R-targeting peptide CP04 ([177Lu]Lu-1b). [177Lu]Lu-1b-4b showed high chemical purity (HPLC ≥ 94%), low Log D7.4 (-4.09 to -4.55) with strong binding affinity to CCK2R (KD 0.097-1.61 nM), and relatively high protein binding (55.6-80.2%) and internalization (40-67%). Biodistribution studies of the novel 177Lu-labeled peptides in tumors (AR42J and A431-CCK2R) showed uptake one- to eight-fold greater than the reference compound CP04 at 1, 24, and 48 h. Rapid clearance and high tumor uptake and retention were established for [177Lu]Lu-2b-4b, making these compounds excellent candidates for theranostic applications against CCK2R-expressing tumors.
Insights
Novel lutetium-177 labeled peptides targeting the cholecystokinin-2 receptor (CCK2R) demonstrate superior tumor uptake and retention. These peptides show promise for peptide receptor radionuclide therapy (PRRT) in CCK2R-expressing cancers.
Area of Science:
- Nuclear Medicine
- Radiopharmaceutical Chemistry
- Oncology
Background:
- Peptide receptor radionuclide therapy (PRRT) offers a targeted approach for cancer eradication.
- The cholecystokinin-2 receptor (CCK2R) is a key molecular target overexpressed in various cancers.
Purpose of the Study:
- To synthesize and evaluate novel lutetium-177 labeled peptides targeting CCK2R.
- To compare the in vivo performance of these new peptides against a reference compound.
Main Methods:
- Synthesis of 177Lu-labeled peptides ([177Lu]Lu-2b-4b) and a reference peptide ([177Lu]Lu-1b).
- In vitro characterization including purity, lipophilicity, CCK2R binding affinity, protein binding, and internalization.
- In vivo biodistribution studies in CCK2R-expressing tumor models (AR42J and A431-CCK2R).
Main Results:
- The novel peptides ([177Lu]Lu-2b-4b) exhibited high purity (≥94%), favorable lipophilicity, and strong CCK2R binding (KD 0.097-1.61 nM).
- These compounds demonstrated significant tumor uptake (1-8 fold higher than reference) and retention at 1, 24, and 48 hours post-injection.
- Rapid clearance from non-target organs was observed.
Conclusions:
- The novel 177Lu-labeled peptides ([177Lu]Lu-2b-4b) show enhanced tumor targeting and retention compared to the reference peptide.
- These findings position these peptides as promising theranostic agents for CCK2R-expressing tumors.
