⁶⁸Ga-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH₂

Background

[PubMed]

Somatostatin (SST) is an inhibitor of the release of somatotropin, glucagon, insulin, gastrointestinal hormones, and other secretory proteins (1). SST is also known as somatotropin release-inhibiting factor (SRIF). SST is a cyclic polypeptide with two biologically active isoforms, SRIF-14 and SRIF-28, of 14 and 28 amino acids, respectively. SRIF has a short plasma half-life of <3 min (2). SST receptors (SSTRs) (G-protein–coupled) have been found on a variety of neuroendocrine tumors and cells of the immune system, and five individual subtypes (SSTR1–SSTR5) have been identified and subsequently cloned from animal and human tissues (3, 4). SST also inhibits cell proliferation and promotes apoptosis through binding to specific cell-surface SSTRs (5).

¹¹¹In-Diethylenetriamine pentaacetic acid-octreotide (¹¹¹In-DTPA-OCT) is an SST analog that, over the last decade, has remained the most widely used radiopharmaceutical for the scintigraphic detection and staging of primary and metastatic neuroendocrine tumors bearing SSTRs and the only FDA approved radiotracer with single-photon emission computed tomography (SPECT) (6). It has also shown promising results in peptide-receptor radionuclide therapy (7). Octreotide (OCT) is a cyclic peptide with eight amino acids. ¹¹¹In-DTPA-OCT binds with high affinity to SSTR2 and SSTR5 and to SSTR3 to a lesser degree, but it does not bind to SSTR1 and SSTR4 (8). A large number of radiolabeled SST analogs have been reported using different radionuclides and different linkers. Currently used targeting SSTR peptides are mainly SSTR2 agonists. Therefore, there is a need for SSTR2 antagonist radioligands (9). p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH₂ (LM3) is a novel selective SSTR2 antagonist. Fani et al. (10) prepared ⁶⁸Ga-1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid-LM3 (⁶⁸Ga-NODAGA-LM3) as a positron emission tomography (PET) imaging agent for SSTR2.

Synthesis

[PubMed]

NODAGA-LM3 was synthesized via standard solid-phase peptide synthesis with a calculated mass of 1,522.6 Da in agreement with mass spectrometry (10). NODAGA was incorporated at the N-terminus of the peptide. NODAGA-LM3 was purified with high-performance liquid chromatography. ⁶⁸Ga was complexed to NODAGA-LM3 by reaction of NODAGA-LM3 with ⁶⁸Ga in sodium acetate (pH 4.0) for 10 min at room temperature. ⁶⁸Ga-NODAGA-LM3 had a >95% radiochemical purity and specific activity of 120 MBq/nmol (3.2 mCi/nmol), with a labeling yield >97%. ⁶⁸Ga-NODAGA-LM3 had a log D value of –2.33 ± 0.22 and a net charge of +1.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Fani et al. (10) reported that ^natGa-NODAGA-LM3 had 50% inhibition concentration (IC₅₀) values of >1,000, 1.3 ± 0.3, >1,000, >1,000, and >1,000 nM for human SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 receptors in competition with ¹²⁵I-SRIF-28, respectively. Immunofluorescence studies showed that the agonist [Tyr³]octreotide (10 nM) triggers receptor internalization whereas ^natGa-NODAGA-LM3 at a much higher concentration (1,000 nM) does not stimulate receptor internalization in HEK-sst2 cells. ^natGa-NODAGA-LM3 was able to inhibit receptor internalization induced by [Tyr³]octreotide.

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

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