Microscale radiosynthesis, preclinical imaging and dosimetry study of [18F]AMBF3-TATE: A potential PET tracer for clinical imaging of somatostatin receptors

Ksenia Lisova; Maxim Sergeev; Susan Evans-Axelsson; Andreea D Stuparu; Seval Beykan; Jeffrey Collins; Jason Jones; Michael Lassmann; Ken Herrmann; David Perrin; Jason T Lee; Roger Slavik; R Michael van Dam

doi:10.1016/j.nucmedbio.2018.04.001

Microscale radiosynthesis, preclinical imaging and dosimetry study of [¹⁸F]AMBF₃-TATE: A potential PET tracer for clinical imaging of somatostatin receptors

Nucl Med Biol. 2018 Jun:61:36-44. doi: 10.1016/j.nucmedbio.2018.04.001. Epub 2018 Apr 20.

Authors

Affiliations

¹ Physics in Biology and Medicine Interdepartmental Graduate Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
² Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
³ Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁴ Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany.
⁵ Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA.
⁶ Department of Chemistry, University of British Columbia, Vancouver, BC, Canada.
⁷ Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA. Electronic address: [email protected].
⁸ Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Ahmanson Translational Imaging Division, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA. Electronic address: [email protected].
⁹ Physics in Biology and Medicine Interdepartmental Graduate Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA. Electronic address: [email protected].

Abstract

Background: Peptides labeled with positron-emitting isotopes are emerging as a versatile class of compounds for the development of highly specific, targeted imaging agents for diagnostic imaging via positron-emission tomography (PET) and for precision medicine via theranostic applications. Despite the success of peptides labeled with gallium-68 (for imaging) or lutetium-177 (for therapy) in the clinical management of patients with neuroendocrine tumors or prostate cancer, there are significant advantages of using fluorine-18 for imaging. Recent developments have greatly simplified such labeling: in particular, labeling of organotrifluoroborates via isotopic exchange can readily be performed in a single-step under aqueous conditions and without the need for HPLC purification. Though an automated synthesis has not yet been explored, microfluidic approaches have emerged for ¹⁸F-labeling with high speed, minimal reagents, and high molar activity compared to conventional approaches. As a proof-of-concept, we performed microfluidic labeling of an octreotate analog ([¹⁸F]AMBF₃-TATE), a promising ¹⁸F-labeled analog that could compete with [⁶⁸Ga]Ga-DOTATATE with the advantage of providing a greater number of patient doses per batch produced.

Methods: Both [¹⁸F]AMBF₃-TATE and [⁶⁸Ga]Ga-DOTATATE were labeled, the former by microscale methods adapted from manual labeling, and were imaged in mice bearing human SSTR2-overexpressing, rat SSTR2 wildtype, and SSTR2-negative xenografts. Furthermore, a dosimetry analysis was performed for [¹⁸F]AMBF₃-TATE.

Results: The micro-synthesis exhibited highly-repeatable performance with radiochemical conversion of 50 ± 6% (n = 15), overall decay-corrected radiochemical yield of 16 ± 1% (n = 5) in ~40 min, radiochemical purity >99%, and high molar activity. Preclinical imaging with [¹⁸F]AMBF₃-TATE in SSTR2 tumor models correlated well with [⁶⁸Ga]Ga-DOTATATE. The favorable biodistribution, with the highest tracer accumulation in the bladder followed distantly by gastrointestinal tissues, resulted in 1.26 × 10^-2 mSv/MBq maximal estimated effective dose in human, a value lower than that reported for current clinical ¹⁸F- and ⁶⁸Ga-labeled compounds.

Conclusions: The combination of novel chemical approaches to ¹⁸F-labeling and microdroplet radiochemistry have the potential to serve as a platform for greatly simplified development and production of ¹⁸F-labeled peptide tracers. Favorable preclinical imaging and dosimetry of [¹⁸F]AMBF₃-TATE, combined with a convenient synthesis, validate this assertion and suggest strong potential for clinical translation.

Keywords: Clinical translation; Microfluidic radiochemistry; Neuroendocrine tumors; SSTR2 imaging; Trifluoroborate; Tumor-targeting peptide.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Boron Compounds / chemistry*
Cell Line, Tumor
Fluorine Radioisotopes*
Lab-On-A-Chip Devices*
Mice
Octreotide / analogs & derivatives*
Octreotide / chemistry
Positron Emission Tomography Computed Tomography*
Radioactive Tracers
Radiochemistry / instrumentation*
Radiometry
Receptors, Somatostatin / metabolism*

Substances

AMBF3-TATE
Boron Compounds
Fluorine Radioisotopes
Radioactive Tracers
Receptors, Somatostatin
Fluorine-18
Octreotide

Abstract

Publication types

MeSH terms

Substances

Grants and funding