Search

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. [ABSTRACT FROM AUTHOR]

Background: Fatty acids derived de novo or taken up from the extracellular space are an essential source of nutrient for cell growth and proliferation. Radiopharmaceuticals including 11C-acetate, and 18F-FAC (2-18F-fluoroacetate), have previously been used to study short-chain fatty acid (SCFA) metabolism. We developed 18F-fluoropivalate (18F-FPIA; 3-18F-fluoro-2,2-dimethylpropionic acid) bearing a gem-dimethyl substituent to assert metabolic stability for studying SCFA metabolism. We report the safety, biodistribution, and internal radiation dosimetry profile of 18F-FPIA in 24 healthy volunteers and the effect of dietary conditions. Materials and methods: Healthy volunteer male and female subjects were enrolled (n = 24), and grouped into 12 fed and 12 fasted. Non-esterified fatty acids (NEFA) and carnitine blood measurements were assessed. Subjects received 159.48 MBq (range, 47.31–164.66 MBq) of 18F-FPIA. Radiochemical purity was > 99%. Safety data were obtained during and 24 h after radiotracer administration. Subjects underwent detailed multiple whole-body PET/CT scanning with sampling of venous bloods for radioactivity and radioactive metabolite quantification. Regions of interest were defined to derive individual and mean organ residence times; effective dose was calculated using OLINDA 1.1. Results: All subjects tolerated 18F-FPIA with no adverse events. Over 90% of radiotracer was present in plasma at 60 min post-injection. The organs receiving highest absorbed dose (in mGy/MBq) were the liver (0.070 ± 0.023), kidneys (0.043 ± 0.013), gallbladder wall (0.026 ± 0.003), and urinary bladder (0.021 ± 0.004); otherwise there was low tissue uptake. The calculated effective dose using mean organ residence times over all 24 subjects was 0.0154 mSv/MBq (SD ± 0.0010). No differences in biodistribution or dosimetry were seen in fed and fasted subjects, though systemic NEFA and carnitine levels reflected fasted and fed states. Conclusion: The favourable safety, imaging, and dosimetric profile makes 18F-FPIA a promising candidate radiotracer for tracing SCFA metabolism. [ABSTRACT FROM AUTHOR]

There is a clinical need for 18 F-labeled somatostatin analogs for the imaging of neuroendocrine tumors (NET), given the limitations of using [ 68 Ga]Ga-DOTA-peptides, particularly with regard to widespread accessibility. We have shown that [ 18 F]fluoroethyl-triazole-[Tyr 3 ]-octreotate ([ 18 F]FET-βAG-TOCA) has favorable dosimetry and biodistribution. As a step toward clinical implementation, we conducted a prospective, noninferiority study of [ 18 F]FET-βAG-TOCA PET/CT compared with [ 68 Ga]Ga-DOTA- peptide PET/CT in patients with NET. Methods: Forty-five patients with histologically confirmed NET, grades 1 and 2, underwent PET/CT imaging with both [ 18 F]FET-βAG-TOCA and [ 68 Ga]Ga-peptide performed within a 6-mo window (median, 77 d; range, 6-180 d). Whole-body PET/CT was conducted 50 min after injection of 165 MBq of [ 18 F]FET-βAG-TOCA. Tracer uptake was evaluated by comparing SUV max and tumor-to-background ratios at both lesion and regional levels by 2 unblinded, experienced readers. A randomized, blinded reading of both scans was also then undertaken by 3 experienced readers, and consensus was assessed at a regional level. The ability of both tracers to visualize liver metastases was also assessed. Results: A total of 285 lesions were detected on both imaging modalities. An additional 13 tumor deposits were seen in 8 patients on [ 18 F]FET-βAG-TOCA PET/CT, and [ 68 Ga]Ga-DOTA-peptide PET/CT detected an additional 7 lesions in 5 patients. Excellent correlation in SUV max was observed between both tracers ( r = 0.91; P < 0.001). No difference was observed between median SUV max across regions, except in the liver, where the median tumor-to-background ratio of [ 18 F]FET-βAG-TOCA was significantly lower than that of [ 68 Ga]Ga-DOTA-peptide (2.5 ± 1.9 vs. 3.5 ± 2.3; P < 0.001). Conclusion: [ 18 F]FET-βAG-TOCA was not inferior to [ 68 Ga]Ga-DOTA-peptide in visualizing NET and may be considered in routine clinical practice given the longer half-life and availability of the cyclotron-produced fluorine radioisotope., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

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, [ 18 F]fluoromethyl-[1,2- 2 H 4 ]choline ([ 18 F]D4-FCH). [ 18 F]D4-FCH has improved protection against choline oxidase, the key choline catabolic enzyme, via a 1 H/ 2 D isotope effect, together with fluorine substitution. Due to the promising mechanistic and safety profiles of [ 18 F]D4-FCH in vitro and preclinically, the radiotracer has transitioned to clinical development. [ 18 F]D4-FCH is a safe positron emission tomography (PET) tracer, with a favourable radiation dosimetry profile for clinical imaging. [ 18 F]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.

Background: Fatty acids derived de novo or taken up from the extracellular space are an essential source of nutrient for cell growth and proliferation. Radiopharmaceuticals including 11 C-acetate, and 18 F-FAC (2- 18 F-fluoroacetate), have previously been used to study short-chain fatty acid (SCFA) metabolism. We developed 18 F-fluoropivalate ( 18 F-FPIA; 3- 18 F-fluoro-2,2-dimethylpropionic acid) bearing a gem-dimethyl substituent to assert metabolic stability for studying SCFA metabolism. We report the safety, biodistribution, and internal radiation dosimetry profile of 18 F-FPIA in 24 healthy volunteers and the effect of dietary conditions., Materials and Methods: Healthy volunteer male and female subjects were enrolled (n = 24), and grouped into 12 fed and 12 fasted. Non-esterified fatty acids (NEFA) and carnitine blood measurements were assessed. Subjects received 159.48 MBq (range, 47.31-164.66 MBq) of 18 F-FPIA. Radiochemical purity was > 99%. Safety data were obtained during and 24 h after radiotracer administration. Subjects underwent detailed multiple whole-body PET/CT scanning with sampling of venous bloods for radioactivity and radioactive metabolite quantification. Regions of interest were defined to derive individual and mean organ residence times; effective dose was calculated using OLINDA 1.1., Results: All subjects tolerated 18 F-FPIA with no adverse events. Over 90% of radiotracer was present in plasma at 60 min post-injection. The organs receiving highest absorbed dose (in mGy/MBq) were the liver (0.070 ± 0.023), kidneys (0.043 ± 0.013), gallbladder wall (0.026 ± 0.003), and urinary bladder (0.021 ± 0.004); otherwise there was low tissue uptake. The calculated effective dose using mean organ residence times over all 24 subjects was 0.0154 mSv/MBq (SD ± 0.0010). No differences in biodistribution or dosimetry were seen in fed and fasted subjects, though systemic NEFA and carnitine levels reflected fasted and fed states., Conclusion: The favourable safety, imaging, and dosimetric profile makes 18 F-FPIA a promising candidate radiotracer for tracing SCFA metabolism.

Purpose : The spatio-molecular distribution of choline and its metabolites in tumors is highly heterogeneous. Due to regulation of choline metabolism by hypoxic transcriptional signaling and other survival factors, we envisage that detection of such heterogeneity in patient tumors could provide the basis for advanced localized therapy. However, non-invasive methods to assess this phenomenon in patients are limited. We investigated such heterogeneity in Non-Small Cell Lung Cancer (NSCLC) with [ 18 F]fluoromethyl-(1,2- 2 H 4 ) choline ([ 18 F]D4-FCH) and positron emission tomography/computed tomography (PET/CT). Experimental design : [ 18 F]D4-FCH (300.5±72.9MBq [147.60-363.6MBq]) was administered intravenously to 17 newly diagnosed NSCLC patients. PET/CT scans were acquired concurrently with radioactive blood sampling to permit mathematical modelling of blood-tissue transcellular rate constants. Comparisons were made with biopsy-derived choline kinase-α (CHKα) expression and diagnostic [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) scans. Results : Oxidation of [ 18 F]D4-FCH to [ 18 F]D4-fluorobetaine was suppressed (48.58±0.31% parent at 60 min) likely due to the deuterium isotope effect embodied within the design of the radiotracer. Early (5 min) and late (60 min) images showed specific uptake of tracer in all 51 lesions (tumors, lymph nodes and metastases) from 17 patients analyzed. [ 18 F]D4-FCH-derived uptake (SUV 60max ) in index primary lesions (n=17) ranged between 2.87-10.13; lower than that of [ 18 F]FDG PET [6.89-22.64]. Mathematical modelling demonstrated net irreversible uptake of [ 18 F]D4-FCH at steady-state, and parametric mapping of the entire tumor showed large intratumorally heterogeneity in radiotracer retention, which is likely to have influenced correlations with biopsy-derived CHKα expression. Conclusions : [ 18 F]D4-FCH is detectable in NSCLC with large intratumorally heterogeneity, which could be exploited in the future for targeting localized therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)