Direct comparison of [18F]AlF-NOTA-JR11 and [18F]AlF-NOTA-octreotide for PET imaging of neuroendocrine tumors: Antagonist versus agonist

Stephen Ahenkorah; Christopher Cawthorne; Erika Murce; Christophe M Deroose; Thomas Cardinaels; Yann Seimbille; Guy Bormans; Maarten Ooms; Frederik Cleeren

doi:10.1016/j.nucmedbio.2023.108338

Direct comparison of [¹⁸F]AlF-NOTA-JR11 and [¹⁸F]AlF-NOTA-octreotide for PET imaging of neuroendocrine tumors: Antagonist versus agonist

Nucl Med Biol. 2023 Mar-Apr:118-119:108338. doi: 10.1016/j.nucmedbio.2023.108338. Epub 2023 Mar 29.

Authors

Stephen Ahenkorah¹, Christopher Cawthorne², Erika Murce³, Christophe M Deroose⁴, Thomas Cardinaels⁵, Yann Seimbille³, Guy Bormans⁶, Maarten Ooms⁷, Frederik Cleeren⁸

Affiliations

¹ NURA Research Group, Belgian Nuclear Research Center (SCK CEN), Mol, Belgium; Radiopharmaceutical Research, Department of Pharmacy and Pharmacology, University of Leuven, Leuven, Belgium.
² Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium.
³ Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands.
⁴ Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium; Nuclear Medicine, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium.
⁵ NURA Research Group, Belgian Nuclear Research Center (SCK CEN), Mol, Belgium; Department of Chemistry, University of Leuven, Leuven, Belgium.
⁶ Radiopharmaceutical Research, Department of Pharmacy and Pharmacology, University of Leuven, Leuven, Belgium.
⁷ NURA Research Group, Belgian Nuclear Research Center (SCK CEN), Mol, Belgium.
⁸ Radiopharmaceutical Research, Department of Pharmacy and Pharmacology, University of Leuven, Leuven, Belgium. Electronic address: frederik.cleeren@kuleuven.be.

PMID: 37018875
DOI: 10.1016/j.nucmedbio.2023.108338

Abstract

Background: [¹⁸F]AlF-NOTA-octreotide is an ¹⁸F-labeled somatostatin analogue which is a good clinical alternative for ⁶⁸Ga-labeled somatostatin analogues. However, radiolabeled somatostatin receptor (SSTR) antagonists might outperform agonists regarding imaging sensitivity of neuroendocrine tumors (NETs). No direct comparison between the antagonist [¹⁸F]AlF-NOTA-JR11 and the agonist [¹⁸F]AlF-NOTA-octreotide as SSTR PET probes is available. Herein, we present the radiosynthesis of [¹⁸F]AlF-NOTA-JR11 and compare its NETs imaging properties directly with the established agonist radioligand [¹⁸F]AlF-NOTA-octreotide preclinically.

Methods: [¹⁸F]AlF-NOTA-JR11 was synthesized in an automated synthesis module. The in vitro binding characteristics (IC₅₀) of [^natF]AlF-NOTA-JR11 and [^natF]AlF-NOTA-octreotide were evaluated and the in vitro stability of [¹⁸F]AlF-NOTA-JR11 was determined in human serum. In vitro cell binding and internalization was performed with [¹⁸F]AlF-NOTA-JR11 and [¹⁸F]AlF-NOTA-octreotide using SSTR2 expressing cells and the pharmacokinetics were evaluated using μPET/CT in mice bearing BON1.SSTR2 tumor xenografts.

Results: Excellent binding affinity for SSTR2 was found for [^natF]AlF-NOTA-octreotide (IC₅₀ of 25.7 ± 7.9 nM). However, the IC₅₀ value for [^natF]AlF-NOTA-JR11 (290.6 ± 71 nM) was 11-fold higher compared to [^natF]AlF-NOTA-octreotide, indicating lower affinity for SSTR2. [¹⁸F]AlF-NOTA-JR11 was obtained in a good RCY (50 ± 6 %) but with moderate RCP of 94 ± 1 %. [¹⁸F]AlF-NOTA-JR11 demonstrated excellent stability in human serum (>95 % after 240 min). 2.7-fold higher cell binding was observed for [¹⁸F]AlF-NOTA-JR11 as compared to [¹⁸F]AlF-NOTA-octreotide after 60 min. μPET/CT images demonstrated comparable pharmacokinetics and tumor uptake between [¹⁸F]AlF-NOTA-JR11 (SUV_max: 3.7 ± 0.8) and [¹⁸F]AlF-NOTA-octreotide (SUV_max: 3.6 ± 0.4).

Conclusions: [¹⁸F]AlF-NOTA-JR11 was obtained in good RCY, albeit with a moderate RCP. The cell binding study showed significant higher binding of [¹⁸F]AlF-NOTA-JR11 compared to [¹⁸F]AlF-NOTA-octreotide, despite the higher IC₅₀ value of AlF-NOTA-JR11. However, pharmacokinetics and in vivo tumor uptake was comparable for both radiotracers. Novel Al¹⁸F-labeled derivatives of JR11 with higher SSTR2 affinity should be developed for increased tumor uptake and NET imaging sensitivity.

Keywords: Al(18)F; Antagonist; NOTA-JR11; NOTA-octreotide; Somatostatin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Mice
Neuroendocrine Tumors* / diagnostic imaging
Octreotide*
Positron-Emission Tomography / methods
Somatostatin

Substances

1,4,7-triazacyclononane-N,N',N''-triacetic acid
Octreotide
Somatostatin