Bench to Bedside Development of [18F]Fluoromethyl-(1,2-2H4)choline ([18F]D4-FCH)

Abstract

Malignant transformation is characterised by aberrant phospholipid metabolism of cancers, associated with the upregulation of choline kinase alpha (CHKα). Due to the metabolic instability of choline radiotracers and the increasing use of late-imaging protocols, we developed a more stable choline radiotracer, [¹⁸F]fluoromethyl-[1,2-²H₄]choline ([¹⁸F]D4-FCH). [¹⁸F]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a ¹H/²D isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [¹⁸F]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [¹⁸F]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [¹⁸F]D4-FCH PET/CT in lung and prostate cancers has shown highly heterogeneous intratumoral distribution and large lesion variability. Treatment with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer patients elicited mixed responses on PET at 12-16 weeks despite predominantly stable radiological appearances. The sum of the weighted tumour-to-background ratios (TBRs-wsum) was associated with the duration of survival.

Keywords: [18F]Fluoromethyl-(1,2-2H4)choline; cell membrane metabolism; choline; dosimetry; in vitro; in vivo; metastatic castrate-resistant prostate cancer; positron emission tomography.

Figure 1

Chemical structure and synthesis of [¹⁸F]D4-FCH, and images of [¹⁸F]D4-FCH-PET in patients with non-small cell lung cancer (NSCLC). (a) Chemical structure of [¹⁸F]D4-FCH. (b) Synthesis of [¹⁸F]D4-FCH. No-carrier-added [¹⁸F]D4-FCH is synthesised by reacting [¹⁸F]fluorobromomethane, synthesised from dibromomethane by [¹⁸F]fluoride-bromide substitution, with D4-N,N-dimethylaminoethanol precursor. (c) [¹⁸F]D4-FCH (top row) and [¹⁸F]FDG PET/CT images (bottom row) in a patient with NSCLC right upper lobe primary (red arrows) demonstrating tumour heterogeneity, and right paratracheal lymph node (green arrows).

Figure 2

[¹⁸F]D4–FCH PET/CT in a left thalamic low-grade glioma 6 months apart (top row, baseline; bottom row, 6 months later) showing minimal tracer uptake above background in the lesion, stable between scans, high signal on T2–weighted MRI imaging with no significant enhancement post-contrast. (Note physiological activity in the choroid plexus). Stable on continued follow-up 6 years later (not shown).

Figure 3

Study design and PET images. (A) Details of the PET study and summary of patients and lesions analysed. (B) Typical [¹⁸F]D4-FCH uptake. MIP, axial, and sagittal views of PET and PET/CT of PT02, showing right external iliac node and T8 bone metastasis (red arrows). (C) Typical [¹⁸F]D4-FCH uptake. MIP, axial, and sagittal views of PET and PET/CT of PT04, showing multiple bone metastases and a left paraaortic nodal metastasis (blue arrows).

Figure 3

Study design and PET images. (A) Details of the PET study and summary of patients and lesions analysed. (B) Typical [¹⁸F]D4-FCH uptake. MIP, axial, and sagittal views of PET and PET/CT of PT02, showing right external iliac node and T8 bone metastasis (red arrows). (C) Typical [¹⁸F]D4-FCH uptake. MIP, axial, and sagittal views of PET and PET/CT of PT04, showing multiple bone metastases and a left paraaortic nodal metastasis (blue arrows).

Figure 4

Response heterogeneity—changes in activity of lesions within individual patients at different times—detected by using [¹⁸F]D4-FCH PET/CT. Representative PET images acquired at baseline (t1), early post-treatment (4–6 weeks; t2), and midtherapy (14–16 weeks; t3) demonstrating decreasing radiotracer uptake in a left seminal vesicle lesion (white arrows) and right iliac bone metastasis (red arrows).

Figure 5

Relative lesional radiotracer uptake at the different time points represented as ‘waterfall’ plots of the percentage variation (%Δ1/2/3) of the tumour-to-background ratio (TBR). We only included patients who completed at least visit 1 and 3 scans within this analysis to avoid bias. The variations were evaluated as follows: %Δt1 = ((t2 − t1)/t1) × 100, n = 28 lesions; %Δt2 = ((t3 − t1)/t1) × 100, n = 48 lesions; %Δt3 = ((t3 − t2)/t2) × 100), n = 28 lesions. TBRBoneMet = SUV_maxBoneMet/SUV_meanBackgBone. TBRSoftTissueMet = SUV_maxSoftTissueMet/SUV_meanBackgMuscle (Backg: background). Soft-tissue metastases are identified with black-outlined bars (rest are bone metastases). Subject P02 is classified as partial responder based on PCWG3.

Figure 6

Response plots of the absolute TBR (per-lesion analysis) evaluated at the three time points, represented as ‘heatmaps’. Of the seven patients who had both t1 and t3 scans, those who did not have t2 scans were excluded from the analysis. N: Node; SV: Seminal vesicle; PD: Peritoneal Disease; B: Bone. *: progressive bone metastasis in patient #2.