The Search for an Alternative to [⁶⁸Ga]Ga-DOTA-TATE in Neuroendocrine Tumor Theranostics: Current State of ¹⁸F-labeled Somatostatin Analog Development

Abstract

The trend to inform personalized molecular radiotherapy with molecular imaging diagnostics, a concept referred to as theranostics, has transformed the field of nuclear medicine in recent years. The development of theranostic pairs comprising somatostatin receptor (SSTR)-targeting nuclear imaging probes and therapeutic agents for the treatment of patients with neuroendocrine tumors (NETs) has been a driving force behind this development. With the Neuroendocrine Tumor Therapy (NETTER-1) phase 3 trial reporting encouraging results in the treatment of well-differentiated, metastatic midgut NETs, peptide radioligand therapy (RLT) with the 177 Lu-labeled somatostatin analog (SSA) [ 177 Lu]Lu-DOTA-TATE is now anticipated to become the standard of care. On the diagnostics side, the field is currently dominated by 68 Ga-labeled SSAs for the molecular imaging of NETs with positron emission tomography-computed tomography (PET/CT). PET/CT imaging with SSAs such as [ 68 Ga]Ga-DOTA-TATE, [ 68 Ga]Ga-DOTA-TOC, and [ 68 Ga]Ga-DOTA-NOC allows for NET staging with high accuracy and is used to qualify patients for RLT. Driven by the demand for PET/CT imaging of NETs, a commercial kit for the production of [ 68 Ga]Ga-DOTA-TATE (NETSPOT) was approved by the U.S. Food and Drug Administration (FDA). The synthesis of 68 Ga-labeled SSAs from a 68 Ge/ 68 Ga-generator is straightforward and allows for a decentralized production, but there are economic and logistic difficulties associated with these approaches that warrant the search for a viable, generator-independent alternative. The clinical introduction of an 18 F-labeled SSTR-imaging probe can help mitigate the shortcomings of the generator-based synthesis approach, but despite extensive research efforts, none of the proposed 18 F-labeled SSAs has been translated past prospective first-in-humans studies so far. Here, we review the current state of probe-development from a translational viewpoint and make a case for a clinically viable, 18 F-labeled alternative to the current standard [ 68 Ga]Ga-DOTA-TATE.

Pharmacokinetics, radiation dosimetry, acute toxicity and automated synthesis of [18F]AmBF3-TATE

“…An advantageous long-term solution may be the adoption of trifluoroborate-based somatostatin analogs [7]. Previously, our laboratory developed [ 18 F]AmBF 3 -TATE, a somatostatin agonist that can be radiolabeled with fluorine-18 using a one-step isotope exchange reaction ( Fig.…”

Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy

“…Fluorine-18, on the contrary, can be mass-produced and distributed daily, thanks to a worldwide network of cyclotrons. Because of this availability, and favorable decay characteristics (T 1/2 = 110 min, 97% β + ), it thus should be noted that some radiotracers based on fluorine-18 have been described ( Figure 9 ) [ 145 ]. The first generations such as 2-[ 18 F]fluoropropionyl- d -Phe 1 -octreotide [ 146 ] or 4-[ 18 F]fluorobenzoyl- d -Phe 1 -octreotide [ 147 ] generally showed unfavorable biokinetic properties (low accumulation and low retention in the tumor).…”

How We Do It: A Multidisciplinary Approach to 177Lu DOTATATE Peptide Receptor Radionuclide Therapy

“…To generate 177 Lu DOTATATE, a somatostatin analog (tyrosine 3 -octreotate) is radiolabeled with 177 Lu by a linker molecule (DOTA). The octreotate component binds to the SSTR and then the entire complex, including the radiolabel 177 Lu, is taken into the NET cells, causing tumor-selective ionizing radiation damage (3,4).…”

“…Initial imaging for PRRT planning, treatment assessment, and restaging should include SSTR imaging for assessing SSTR expression, which is critical to the efficacy of PRRT (31,32). At present, 68 Ga-labeled somatostatin analogs, such as DOT-ATATE, DOTA-d-Phe1-Tyr3-octreotide (DOTATOC), and DOTA-Nal3-octreotide (or DOTANOC), are the predominant SSTR contrast materials, with commercial generatorproduction kits available for 68 Ga DOTATATE and Food and Drug Administration approval of 68 Ga DOTATATE and 68 Ga DOTATOC as PET contrast materials (4,33). Radionuclides, such as fluorine 18 ( 18 F) and copper 64 ( 64 Cu), are more easily transported from centralized production sites because of longer half-lives and therefore offer logistical advantages compared to 68 Ga, which requires local generator production.…”