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Comparison Study of Two Differently Clicked ¹⁸F-Folates-Lipophilicity Plays a Key Role.

ABSTRACT: Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable ¹⁸F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel ¹⁸F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the ¹⁸F-folates was investigated. ¹⁸F-Ala-folate and ¹⁸F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of the strain-promoted clicked ¹⁸F-DBCO-folate (logD = 0.6) contributed to a higher non-specific binding in cell internalization studies. In the following in vivo PET imaging studies, FR-positive tumors could not be visualized in a maximum intensity projection images. Compared with ¹⁸F-DBCO-folate, ¹⁸F-Ala-folate (logD = -1.4), synthesized by the copper-catalyzed click reaction, exhibited reduced lipophilicity, and as a result an improved in vivo performance and a clear-cut visualization of FR-positive tumors. In view of high radiochemical yield, radiochemical purity and favorable pharmacokinetics, ¹⁸F-Ala-folate is expected to be a promising candidate for FR-PET imaging.

SUBMITTER: Kettenbach K

PROVIDER: S-EPMC5874726 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Comparison Study of Two Differently Clicked 18F-Folates-Lipophilicity Plays a Key Role.

Kettenbach Kathrin K Reffert Laura M LM Schieferstein Hanno H Pektor Stefanie S Eckert Raphael R Miederer Matthias M Rösch Frank F Ross Tobias L TL

Pharmaceuticals (Basel, Switzerland) 20180317 1

Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable 18F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel 18F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacoki ...[more]

PMID: 29562610

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Project description:Purpose[18F]FDG PET/CT in multiple myeloma (MM) is currently the best technology to demonstrate patchy and extramedullary disease. However, [18F]FDG PET has some limitations, and imaging with alternative tracers should be explored. In this study, we aimed to evaluate the performance of [18F]fluciclovine PET compared to [18F]FDG PET in newly diagnosed MM patients.ProceduresThirteen newly diagnosed transplant eligible MM patients were imaged both with [18F]FDG PET/CT and [18F]fluciclovine PET/CT within 1 week in a prospective study. The subjects were visually assessed positive or negative for disease. The number of lesions and the SUVmax of selected lesions were measured for both tracers. Furthermore, tracer uptake ratios were obtained by dividing lesion SUVmax by blood or bone marrow SUVmax. Between-group differences and correlations were assessed with paired t-tests and Pearson tests. Bone marrow SUVs were compared to bone marrow plasma cell percentage in biopsy samples.ResultsNine subjects were assessed positively by [18F]FDG PET (69%) and 12 positives by [18F]fluciclovine PET (92%). All positive subjects had [18F]fluciclovine scans that were qualitatively scored as easier to interpret visually than the [18F]FDG scans. The number of lesions was also higher; seven of nine subjects with distinct hot spots on [18F]fluciclovine PET had fewer or no visible lesions on [18F]FDG PET. The mean lesion SUVmax values were 8.2 and 3.8 for [18F]fluciclovine and [18F]FDG, respectively. The mean tumour to blood values were 6.4 and 2.0 for [18F]fluciclovine and [18F]FDG, and the mean ratios between tumour and bone marrow were 2.1 and 1.5 for [18F]fluciclovine and [18F]FDG. The lesion SUVmax and ratios were significantly higher for [18F]fluciclovine (all p < 0.01). Local [18F]fluciclovine SUVmax or SUVmean values in os ilium and the percentage of plasma cells in bone marrow biopsies were linearly correlated (p = 0.048). There were no significant correlations between [18F]FDG SUVs and plasma cells (p = 0.82).ConclusionsBased on this pilot study, [18F]fluciclovine is a promising tracer for MM. The visual and semi-quantitative evaluations indicate that [18F]fluciclovine PET/CT can out-perform [18F]FDG PET/CT at diagnosis.

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Comparison Study of Two Differently Clicked ¹⁸F-Folates-Lipophilicity Plays a Key Role.

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Comparison Study of Two Differently Clicked <sup>18</sup>F-Folates-Lipophilicity Plays a Key Role.

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