Preclinical Incorporation Dosimetry of [18F]FACH-A Novel 18F-Labeled MCT1/MCT4 Lactate Transporter Inhibitor for Imaging Cancer Metabolism with PET

Abstract

Overexpression of monocarboxylate transporters (MCTs) has been shown for a variety of human cancers (e.g., colon, brain, breast, and kidney) and inhibition resulted in intracellular lactate accumulation, acidosis, and cell death. Thus, MCTs are promising targets to investigate tumor cancer metabolism with positron emission tomography (PET). Here, the organ doses (ODs) and the effective dose (ED) of the first ¹⁸F-labeled MCT1/MCT4 inhibitor were estimated in juvenile pigs. Whole-body dosimetry was performed in three piglets (age: ~6 weeks, weight: ~13-15 kg). The animals were anesthetized and subjected to sequential hybrid Positron Emission Tomography and Computed Tomography (PET/CT) up to 5 h after an intravenous (iv) injection of 156 ± 54 MBq [¹⁸F]FACH. All relevant organs were defined by volumes of interest. Exponential curves were fitted to the time-activity data. Time and mass scales were adapted to the human order of magnitude and the ODs calculated using the ICRP 89 adult male phantom with OLINDA 2.1. The ED was calculated using tissue weighting factors as published in Publication 103 of the International Commission of Radiation Protection (ICRP103). The highest organ dose was received by the urinary bladder (62.6 ± 28.9 µSv/MBq), followed by the gall bladder (50.4 ± 37.5 µSv/MBq) and the pancreas (30.5 ± 27.3 µSv/MBq). The highest contribution to the ED was by the urinary bladder (2.5 ± 1.1 µSv/MBq), followed by the red marrow (1.7 ± 0.3 µSv/MBq) and the stomach (1.3 ± 0.4 µSv/MBq). According to this preclinical analysis, the ED to humans is 12.4 µSv/MBq when applying the ICRP103 tissue weighting factors. Taking into account that preclinical dosimetry underestimates the dose to humans by up to 40%, the conversion factor applied for estimation of the ED to humans would rise to 20.6 µSv/MBq. In this case, the ED to humans upon an iv application of ~300 MBq [¹⁸F]FACH would be about 6.2 mSv. This risk assessment encourages the translation of [¹⁸F]FACH into clinical study phases and the further investigation of its potential as a clinical tool for cancer imaging with PET.

Keywords: MCT1/MCT4 lactate transporter inhibitor; OLINDA; [18F]FACH; image-based internal dosimetry; preclinical radiopharmaceutical dosimetry; radiation safety.

Figure 1

Examples of the mono-, bi-, or tri-exponential fits, including exponential fit equations and parameters of fit goodness (R-squared and squared error) of the human scale time–activity data using the EXM-Module of OLINDA. All fits are presented in the Supplementary Materials (Figures S1–S3).

Figure 2

Whole body dynamic positron emission tomography (PET) images in coronal (upper row) and sagittal (lower row) views of pig 1 after intravenous (iv) application of 191 MBq [¹⁸F]FACH.

Figure 3

PET image with volumes of interest (VOIs) superimposed in (a) coronal, (b) sagittal, and (c) transversal views. The left panel, pig 1, obtained at 42 min post injection (p.i.), shows the organs except for the peripheral bone, whereas the right panel, pig 2, obtained at 56 min. p.i., shows all delineated organs. (The gray scale in the middle refers to the original quantitative PET data, not to the colored VOI structures).

Figure 4

Chemical structure of [¹⁸F]FACH.

Figure 5

The animals were placed in a plastic trough and a special head rest to guarantee reproducible positioning and avoid the movement of artefacts.

Figure 6

PET/CT imaging protocol comprising a dynamic and static part with increasing duration per bed position (BP) to compensate for decay and, thus, decreasing count statistics, preceded by a low-dose CT (LD-CT) for attenuation correction and anatomical orientation, respectively. Positioning of the animal in the PET field of view.