Automated radiosynthesis and preclinical evaluation of two new PSMA-617 derivatives radiolabelled via [18F]AlF2+ method.

BACKGROUND: In the last decade the development of new PSMA-ligand based radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research. The most promising derivative in terms of interaction with the antigen and clinical properties has been found to be "PSMA-617", and its lutetium-177 radiolabelled version has recently been approved by EU and USA regulatory agencies for therapeutic purposes. For the above reasons, the development of new derivatives of PSMA-617 radiolabelled with fluorine-18 may still be of great interest. This paper proposes the comparison of two different PSMA-617 derivatives functionalized with NODA and RESCA chelators, respectively, radiolabelled via [18F]AlF2+ complexation. RESULTS: The organic synthesis of two PSMA-617 derivatives and their radiolabelling via [18F]AlF2+ complexation resulted to proceed efficiently and successfully. Moreover, stability in solution and in plasma has been evaluated. The whole radiosynthesis procedure has been fully automated, and the final products have been obtained with radiochemical yield and purity potentially suitable for clinical studies. The biodistribution of the two derivatives was performed both in prostate cancer and glioma tumour models. Compared with the reference [18F]F-PSMA-1007 and [18F]F-PSMA-617-RESCA, [18F]F-PSMA-617-NODA derivative showed a higher uptake in both tumors, faster clearance in non-target organs, and lower uptake in salivary glands. CONCLUSION: PSMA-617 NODA and RESCA derivatives were radiolabelled successfully via [18F]AlF2+ chelation, the former being more stable in solution and human plasma. Moreover, preclinical biodistribution studies showed that [18F]F-PSMA-617-NODA might be of potential interest for clinical applications.

The "digital biopsy" in non-small cell lung cancer (NSCLC): a pilot study to predict the PD-L1 status from radiomics features of [18F]FDG PET/CT.

PURPOSE: The present pilot study investigates the putative role of radiomics from [18F]FDG PET/CT scans to predict PD-L1 expression status in non-small cell lung cancer (NSCLC) patients. METHODS: In a retrospective cohort of 265 patients with biopsy-proven NSCLC, 86 with available PD-L1 immunohistochemical (IHC) assessment and [18F]FDG PET/CT scans have been selected to find putative metabolic markers that predict PD-L1 status (< 1%, 1-49%, and ≥ 50% as per tumor proportion score, clone 22C3). Metabolic parameters have been extracted from three different PET/CT scanners (Discovery 600, Discovery IQ, and Discovery MI) and radiomics features were computed with IBSI compliant algorithms on the original image and on images filtered with LLL and HHH coif1 wavelet, obtaining 527 features per tumor. Univariate and multivariate analysis have been performed to compare PD-L1 expression status and selected radiomic features. RESULTS: Of the 86 analyzed cases, 46 (53%) were negative for PD-L1 IHC, 13 (15%) showed low PD-L1 expression (1-49%), and 27 (31%) were strong expressors (≥ 50%). Maximum standardized uptake value (SUVmax) demonstrated a significant ability to discriminate strong expressor cases at univariate analysis (p = 0.032), but failed to discriminate PD-L1 positive patients (PD-L1 ≥ 1%). Three radiomics features appeared the ablest to discriminate strong expressors: (1) a feature representing the average high frequency lesion content in a spherical VOI (p = 0.009); (2) a feature assessing the correlation between adjacent voxels on the high frequency lesion content (p = 0.004); (3) a feature that emphasizes the presence of small zones with similar grey levels inside the lesion (p = 0.003). The tri-variate linear discriminant model combining the three features achieved a sensitivity of 81% and a specificity of 82% in the test. The ability of radiomics to predict PD-L1 positive patients was instead scarce. CONCLUSIONS: Our data indicate a possible role of the [18F]FDG PET radiomics in predicting strong PD-L1 expression; these preliminary data need to be confirmed on larger or single-scanner series.

Treatment response assessment in [18F]FDG-PET/CT oncology scans: Impact of count statistics variation and reconstruction protocol.

PURPOSE: To investigate influences of reconstruction algorithms and count statistics variation on quantification and treatment response assessment in cancer patients, by using a large field of view-FOV scanner. METHODS: 54 cancer patients underwent PET/CT scan: 1) at baseline: 1.5 min/FOV, reconstructed by ordered-subset expectation maximization + point-spread-function-OSEM-PSF and bayesian penalised-likelihood-BPL algorithm 2) at restaging: 2 min/FOV, reconstructed also at 1.5 and 1 min/FOV, using OSEM-PSF and BPL. SUL (lean-body mass SUV) peak and max were measured for each target-lesion (n = 59). Differences in quantification obtained from datasets with different reconstruction algorithms and different time/FOV were evaluated. For any pair of PET datasets, metabolic response was assessed by using SULpeak, with a threshold of 30% in variation considered as significant. RESULTS: Both at baseline and restaging, SULpeak and max values were higher in BPL reconstructions than in OSEM-PSF (p < 0.0001). SULpeak at different time/FOV reconstructions showed no statistically significant differences both with OSEM-PSF and BPL; SULmax depended on acquisition time (p < 0.05). In 56/59 lesions (95%) therapy response was concordant regardless count statistics variation and reconstruction algorithm; 2/59 (3%) showed different responses according to count statistics, both for OSEM-PSF and BPL; in 1/59 lesion (2%) response was different depending on reconstruction algorithm used. CONCLUSIONS: BPL provided higher SULpeak and max than OSEM-PSF. With a large FOV/high sensitivity scanner, variation of time/FOV in restaging PET scans gave stable and reproducible results in terms of SULpeak, both for OSEM-PSF and BPL. Thus, metabolic response defined by SULpeak variation proved to be quite independent from count statistics.

Non-peptide NK1 receptor ligands based on the 4-phenylpyridine moiety.

The quinoline nucleus of the previously described 4-phenylquinoline-3-carboxamides NK(1) receptor ligands 7 has been transformed into either substituted or azole-(i.e., triazole or tetrazole) fused pyridine moieties of compounds 9 and 10, respectively, in order to obtain NK(1) receptor ligands showing lower molecular weight or higher hydrophilicity. The program of molecular manipulations produced NK(1) receptor ligands showing affinity in the nanomolar range. In particular, 4-methyl-1-piperazinyl derivative 9j showed an IC(50) value of 4.8 nM and was proved to behave as a NK(1) antagonist blocking Sar(9)-SP-sulfone induced proliferation and migration of microvascular endothelial cells. Therefore, compound 9j has been labeled with [(11)C]CH(3)I (t(1/2)=20.4 min, ß(+)=99.8%) starting from the corresponding des-methyl precursor 9i using with a radiochemical yield of about 10% (not decay corrected) and a specific radioactivity>1 Ci/µmol in order to be used as a radiotracer in next PET studies.

Synthesis and carbon-11 labeling of (R)- and (S)-thionisoxetine, norepinephrine reuptake inhibitors, potential radioligands for positron emission tomography.

Standards and des-methyl precursors of (R)- and (S)-thionisoxetine, potent and selective norepinephrine reuptake inhibitors, were synthesized and radiolabeled with carbon-11. Both enantiomers of the N-methyl-3-(2-thiomethylphenoxy)-3-phenylpropanamine and the 3-(2-thiomethylphenoxy)-3-phenylpropylamine were obtained via multi-step syntheses, while the radiosyntheses were carried out using [11C]CH3I. The radiochemical yields were 26%, decay corrected and the specific radioactivity ranging from 2 to 3 Ci/micromol. The HPLC analyses were performed using a chiral column: during the radiolabeling, no racemization occurred and the isomers were synthesized with high enantiomeric purity.

Synthesis, labeling, and biological evaluation of halogenated 2-quinolinecarboxamides as potential radioligands for the visualization of peripheral benzodiazepine receptors.

The previous exploration of the structure-affinity relationships concerning 4-phenyl-2-quinolinecarboxamide peripheral benzodiazepine receptor (PBR) ligands 6 showed as an interesting result the importance of the presence of a chlorine atom in the methylene carbon at position 3 of the quinoline nucleus. The subnanomolar PBR affinity shown by N-benzyl-3-chloromethyl-N-methyl-4-phenyl-2-quinolinecarboxamide (6b) suggested its chlorine atom to be replaced with other halogens in order to optimize the interaction of the quinolinecarboxamide derivatives with PBR and to develop suitable candidates for positron emission tomography (PET) or single photon emission computed tomography (SPECT) studies. The binding studies led to the discovery of fluoromethyl derivative 6a, which showed an IC50 value of 0.11 nM and is, therefore, one of the most potent PBR ligands so far described. Fluoromethyl derivative 6a has been labeled with 11C (t1/2=20.4 min, beta+=99.8%) starting from the corresponding des-methyl precursor (14) using [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF with a 35-40% radiochemical yield (corrected for decay) and 1.5 Ci/micromol of specific radioactivity. Ex vivo rat biodistribution and inhibition (following intravenous pre-administration of PK11195) studies showed that [11C]6a rapidly and specifically accumulated in PBR-rich tissues such as heart, lung, kidney, spleen, and adrenal, and at a lower level in other peripheral organs and in the brain. The images obtained in mouse with small animal YAP-(S)PET essentially confirmed the result of the ex vivo biodistribution experiments. The biological data suggest that [11C]6a is a promising radioligand for peripheral benzodiazepine receptor PET imaging in vivo.

11C-Radiosynthesis and preliminary human evaluation of the disposition of the ACE inhibitor [11C]zofenoprilat.

(4S)-1-[(S)-3-Mercapto-2-methylpropanoyl]-4-phenylthio-L-proline (Zofenoprilat, 2), the active metabolite of the potent ACE inhibitor Zofenopril Calcium (1), was labelled with carbon-11 (t1/2=20.4 min) to evaluate its pharmacokinetics behaviour in human body using Positron Emission Tomography (PET). [11C]2 labelling procedures were based on the use of immobilized Grignard reagent and the acylation of (S)-4-phenylthio-L-proline methyl ester (5) with 11C-labelled methacryloyl chloride, followed by a Michael addition with thiobenzoic acid. The radiochemical yield was 5-10% (EOB, decay corrected) and specific radioactivity ranged from 0.5 to 1.5 Ci/micromol (18.5-55.5 GBq/micromol). Preliminary in vivo human evaluation of [11C]2 showed that the drug accumulates in organs which express high levels of ACE, like lungs and kidneys, and in organs involved in drug metabolism such as the liver and gall bladder. Results of the distribution of [11C]2 showed a measurable concentration of the drug in the target tissues such as the kidney and to a minor extent, the heart, where it can afford organ protection.

Automation of [11C]acyl chloride syntheses using commercially available 11C-modules.

In implementing published procedures for the incorporation of [11C]carbon dioxide on the immobilized Grignard reagents for the radiosynthesis of [11C]acyl chlorides, several modifications on a commercial PET tracer synthesizer module for 11C-methylations were made to obtain reliable and reproducible production processes for routine clinical applications. High yields of [carbonyl-11C]WAY-100635 and [11C]zofenoprilat were obtained via 11C-carboxylation using [carbonyl-11C]cyclohexanecarbonyl chloride and 2-methyl-[l-11C]acryloyl chloride prepared with the modified module.