Automated synthesis of [68Ga]Ga-FAPI-46 without pre-purification of the generator eluate on three common synthesis modules and two generator types

Abstract

Background The recent development of quinoline-based radiotracers, which act as fibroblast activation protein inhibitors (FAPIs), has shown promising preclinical and clinical advantages. [68Ga]Ga-FAPI-46 is a new radiotracer for in vivo detection of the fibroblast activation protein by positron emission tomography (PET). Recently, the automated synthesis of [68Ga]Ga-FAPI-46 was reported based on pre-concentration and purification of the generator eluate by using a cation exchange-cartridge. Our aim was to simplify the synthesis and shorten the automated synthesis of [68Ga]Ga-FAPI-46 to make it accessible and thus even more attractive to a broader clinical and scientific community. Results We developed and evaluated the GMP compliant automatic synthesis of [68Ga]Ga-FAPI-46 using two different 68Ge/68Ga generators (an Eckert & Ziegler, GalliaPharm generator, 1.85 GBq/50 mCi and an iThemba generator, 1.85 GBq/50 mCi) Somerset West, South Africa) and three different commercial and customized systems: the EasyOne module from Trasis; the GaSy module from Synthra with a customized synthesis template and a customized single use cassette. Additionally, the automatic synthesis of [68Ga]Ga-FAPI-46 was established on a GallElut synthesis module from Scintomics with fixed tubing. Conclusions Independent of the synthesis modules or the generators employed we were able to complete the synthesis of [68Ga]Ga-FAPI-46 in 12 min including the process of purification and formulation. In all cases, the final products showed more than 99.5% chemical purity and the radiochemical yield reached around 92.5% (decay corrected). All quality control parameters (e.g. sterility, stability and radiochemical purity) were conform to the European Pharmacopoeia.

Fibroblast Activation Protein Inhibitor (FAPI)-Based Theranostics—Where We Are at and Where We Are Heading: A Systematic Review

“… Chemical structures of FAPI precursors used in clinical application with nuclides in brackets [ 62 ]. Reprinted/Adapted from ref.…”

Automated radiolabeling and handling of 177Lu‐ and 225Ac‐PSMA‐617 using a robotic pipettor

“…These systems, also known as modules, provide users with a high degree of flexibility with respect to the chemistry and processes they can perform, allowing users to manufacture a wide range of products. [1][2][3][4] While processes involving F-18 and C-11 typically make use of many of these features, such as semi-preparative HPLC purification of the intermediate or final compound, radiopharmaceuticals labeled with a radiometal often do not. 1,5 For example, most manual radiosynthetic methods involving Zr-89, Lu-177, or Ac-225 are composed of a series of solution transfers to and from various vials using pipettes.…”

“…[1][2][3][4] While processes involving F-18 and C-11 typically make use of many of these features, such as semi-preparative HPLC purification of the intermediate or final compound, radiopharmaceuticals labeled with a radiometal often do not. 1,5 For example, most manual radiosynthetic methods involving Zr-89, Lu-177, or Ac-225 are composed of a series of solution transfers to and from various vials using pipettes. When considering automation, the radiochemist adapts these manual processes to automated radiosynthesis platforms that are composed of transfer lines and valves.…”

“…A growing variety of commercially available radiosynthesis systems offer automated radiolabeling, purification, and formulation of radiopharmaceuticals. These systems, also known as modules, provide users with a high degree of flexibility with respect to the chemistry and processes they can perform, allowing users to manufacture a wide range of products 1–4 . While processes involving F‐18 and C‐11 typically make use of many of these features, such as semi‐preparative HPLC purification of the intermediate or final compound, radiopharmaceuticals labeled with a radiometal often do not 1,5 .…”

Microfluidic-based production of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC using the cassette-based iMiDEV™ microfluidic radiosynthesizer

“…The radiolabeling of DOTA chelators with the 68 Ga-radionuclide requires high temperatures (León-Rodríguez and Kovacs 2008 ). Currently, most conventional methods use cassette-based approaches to synthesize 68 Ga-radiotracers, which requires 40–50 µg (Nelson et al 2022 ; Alfteimi et al 2022 ) of precursors for radiolabeling. The amount of precursor can be reduced by applying microfluidic-based synthesis.…”