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In vivo imaging of MMPs is of great (pre)clinical interestandcan potentially be realized with modern three-dimensional and noninvasivein vivo molecular imaging techniques such as positron emission tomography(PET). Consequently, MMP inhibitors (MMPIs) radiolabeled with positronemitting nuclides (e.g., 18F) represent a suitable toolfor the visualization of activated MMPs with PET. On the basis ofour previous work and results regarding radiolabeled and unlabeledderivatives of the nonselective MMPIs, we discovered a new class offluorinated MMPIs with a triazole-substituted hydroxamate substructure.These novel MMPIs are characterized by an increased hydrophilicitycompared with the lead structures and excellent MMP inhibition potenciesfor MMP-2, MMP-8, MMP-9, and MMP-13 (IC50= 0.006–107nM). Therefore, one promising fluorinated triazole-substituted hydroxamate(30b) was selected and resynthesised as its 18F-labeled version to yield the potential PET radioligand [18F]30b. The biodistributionbehavior of this novel compound was investigated with small animalPET. [ABSTRACT FROM AUTHOR]

Abstract: The CGS 27023A derivative (R)-2-(N-((6-fluoropyridin-3-yl)methyl)-4-methoxyphenyl-sulphonamido)-N-hydroxy-3-methylbutanamide 1a was identified as a very potent matrix metalloproteinase inhibitor. Here, we describe a one-step radiosynthesis of the target compound [18F]1a. The syntheses of [18F]1a resulted in a radiochemical yield of 12.1±5.9% (decay-corrected), a radiochemical purity of 98.8±0.6%, and a specific activity of 39±27GBq/μmol at the end of synthesis within 160±18min from the end of radionuclide production (n=5). Initial small-animal PET studies in wild-type mice (C57/BL6) showed no unfavourable tissue accumulation of [18F]1a. [Copyright &y& Elsevier]

Summary: The CGS 25966 derivative (R)-2-(N-Benzyl-4-(2-[18F]fluoroethoxy)phenyl-sulphonamido)-N-hydroxy-3-methylbutanamide [18F]9 represents a very potent radiolabelled matrix metalloproteinase inhibitor. For first human PET studies it is mandatory to have a fully automated radiosynthesis and a straightforward precursor synthesis available. The realisation of both requirements is reported herein. In particular, the corresponding precursor 8 was obtained in a reliable 7 step synthesis with an overall chemical yield of 2.3%. Furthermore, the target compound [18F]9 was prepared with a radiochemical yield of 14.8±3.9% (not corrected for decay). [ABSTRACT FROM AUTHOR]

Abstract: It is assumed that the regulation of cardiac endothelin (ET) receptor density is abnormal in heart diseases. From that perspective, an ET receptor radioligand is needed to assess ET receptor density in vivo. The nonpeptidyl ETA receptor antagonist PD 169390 was labelled with radioiodine to give a putative radioligand for SPECT. Labelling with [125I]iodide and [123I]iodide was accomplished with good to excellent radiochemical yields. The affinities of the nonradioactive reference and those of selected precursor compounds for ETA receptors were determined, using [125I]iodine labelled endothelin-1 with mouse ventricular membranes. All employed substances exhibited potent in vitro pharmacological characteristics with K i values comparable to that of the lead compound PD 156707. Biodistribution studies and scintigraphic imaging experiments in mice, however, showed no significant uptake of the [123I] derivative in the heart. [Copyright &y& Elsevier]

Improving imaging-based response after neoadjuvant chemotherapy (NAC) in breast cancer assessment could obviate histologic confirmation of pathologic complete response (pCR) and facilitate deescalation of chemotherapy or surgery. Fibroblast activation protein inhibitor (FAPI) PET/MRI is a promising novel molecular imaging agent for the tumor microenvironment with intense uptake in breast cancer. We assessed the diagnostic performance of follow-up breast 68 Ga-FAPI-46 ( 68 Ga-FAPI) PET/MRI in classifying the response status of local breast cancer and lymph node metastases after completion of NAC and validated this approach immunohistochemically. Methods: In women who completed NAC for invasive breast cancer, follow-up 68 Ga-FAPI PET/MRI and corresponding fibroblast activation protein (FAP) immunostainings were retrospectively analyzed. Metrics of 68 Ga-FAPI uptake and FAP immunoreactivity in women with or without pCR were compared using the Mann-Whitney U test. Diagnostic performance to detect remnant invasive cancer was calculated for tracer uptake metrics using receiver-operating-characteristic curves and for masked readers' visual assessment categories of PET/MRI and MRI alone. Results: Thirteen women (mean age ± SD, 47 ± 9 y) were evaluated. Seven of the 13 achieved pCR in the breast and 6 in the axilla. FAP immunoreactivity was significantly associated with response status. The 68 Ga-FAPI PET/MRI mean breast tumor-to-background ratio was 0.9 (range, 0.6-1.2) for pCR and 2.1 (range, 1.4-3.1) for no pCR ( P = 0.001). Integrated PET/MRI could classify breast response correctly in all 13 women based on readers' visual assessment or tumor-to-background ratio. Evaluation of MRI alone resulted in at least 2 false-positives. For lymph nodes, PET/MRI readers had at least 2 false-negative classifications, whereas MRI alone resulted in 2 false-negatives and 1 false-positive. Conclusion: To our knowledge, this was the first analysis of 68 Ga-FAPI PET/MRI for response assessment after NAC for breast cancer. The diagnostic performance of PET/MRI in a small study sample trended toward a gain over MRI alone, clearly supporting future prospective studies., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Unlabelled: We evaluated the diagnostic value and accuracy of prostate-specific membrane antigen (PSMA) PET for the intraprostatic delineation of prostate cancer before prostatectomy., Methods: We identified 6 patients with biopsy-proven high-risk prostate cancer who were referred for (68)Ga-PSMA PET/CT before radical prostatectomy to rule out metastasis. After prostatectomy, a histologic map of the prostate was reconstructed. The histologic extent and Gleason score of each segment of the prostate were compared with (68)Ga-PSMA PET images resliced to the histologic axis. Sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios were calculated. The SUV of each segment was measured, and median values were compared., Results: Of the 132 segments, 112 were eligible for analysis. The correlation of histologic results with (68)Ga-PSMA PET images showed a specificity and sensitivity of 92%. The positive and negative likelihood ratio and the positive and negative predictive value for detection of prostate cancer on (68)Ga-PSMA PET were 11.5, 0.09, 96%, and 85%, respectively. The median SUVmax of true-positive prostate segments was significantly higher than that of true-negative segments (11.0 ± 7.8 vs. 2.7 ± 0.9, P< 0.001), and a cutoff of 4 revealed a sensitivity and specificity of 86.5% and an accuracy of 87.5%., Conclusion: These preliminary results show that the intraprostatic localization and extent of prostate cancer may be estimated by (68)Ga-PSMA PET. This imaging method may be helpful for identifying target lesions before prostate biopsy and may support decision making before focal or radical therapy., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Radiolabeled C-5-disubstituted pyrimidine-2,4,6-triones have recently been suggested by our group as a class of potent matrix metalloproteinase (MMP) targeted radiotracers that can noninvasively visualize activated MMPs by means of positron emission tomography (PET). MMPs belong to the zinc- and calcium-dependent endopeptidases which are involved in the proteolytic degradation of components of the extracellular matrix (ECM) but also are capable of processing and releasing bioactive molecules such as growth factors, proteinase inhibitors, and cytokines. Locally increased levels of activated MMPs modulate and contribute to the progression of various diseases, such as cancer, atherosclerosis, stroke, arthritis, and others. Therefore, activated MMPs are suitable biological targets for the specific and noninvasive visualization of aforementioned pathologies in vivo. On the basis of our recent results, we here describe a series of new fluorinated pyrimidine-2,4,6-triones of the second generation with maintained MMP inhibition potencies (IC(50) = 4-605 nM), which are fine-tuned toward more hydrophilic versions, and show the improved biodistribution behavior of one selected radiofluorinated pyrimidine-2,4,6-trione by means of small-animal PET.