Treatment with immune checkpoint inhibitors has improved both progressionfree survival and overall survival in a subset of patients with tumors. However, the selection of patients who benefit from ...immune checkpoint inhibitor treatment remains challenging. Positron Emission Tomography (PET) is a non-invasive molecular imaging tool that offers a promising alternative to the current IHC for detecting the PD-L1 expression in malignant cells in vivo, enabling patient selection and predicting the response to individual patient immunotherapy treatment.
Herein, we report the development of novel
Flabeled pyridine-2-carboxamide derivatives
F2 and
F3 as small-molecule probes for imaging immune checkpoint (PD-1/PD-L1) in cancer using PET.
F2 and
F3 were prepared by a one-step radiofluorination in 44 ± 5% and 30 ± 4% radiochemical yield and > 98% radiochemical purity for a potential clinical translation. The total synthesis time, including HPLC purification, was less than 45 min.
F2 and
F3 showed excellent stability in injection solution and a significant accumulation and retention in PD-1/PD-L1 expressing MDA-MB-231 breast cancer and in HeLa cervix carcinoma cells (2- 5 cpm/1000 cells). In addition, autoradiographic analysis and inhibition experiments on tumor slices confirm the potential of both compounds as specific imaging probes for the PD-1/PD-L1 axis in tumors.
The in vitro evaluation in PD-L1 expressing cells together with results from autoradiographic analysis in PD-L1 positive tumor sections, suggest that
F2 and
F3 could be potential imaging probes for assessing PD-L1 expression in tumors and warrant further biological evaluations in vivo.
PET/CT with
F-FDG is an integral component in the primary staging of most lymphomas. However, its utility is limited in marginal-zone lymphoma (MZL) because of inconsistent
F-FDG avidity. One ...diagnostic alternative could be the targeting of C-X-C motif chemokine receptor 4 (CXCR4), shown to be expressed by MZL cells. This study investigated the value of adding CXCR4-directed
Ga-pentixafor PET/CT to conventional staging.
Twenty-two newly diagnosed MZL patients were staged conventionally and with CXCR4 PET/CT. Lesions identified exclusively by CXCR4 PET/CT were biopsied as the standard of reference and compared with imaging results. The impact of CXCR4-directed imaging on staging results and treatment protocol was assessed.
CXCR4 PET/CT correctly identified all patients with viable MZL and was superior to conventional staging (
< 0.001). CXCR4-directed imaging results were validated by confirmation of MZL in 16 of 18 PET-guided biopsy samples. Inclusion of CXCR4 PET/CT in primary staging significantly impacted staging results in almost half of patients and treatment protocols in a third (upstaging,
= 7; downstaging,
= 3; treatment change,
= 8;
< 0.03).
CXCR4 PET/CT is a suitable tool in primary staging of MZL and holds the potential to improve existing diagnostic algorithms.
We have recently reported on our experience with C-X-C-motif chemokine receptor 4 (CXCR4)-directed radioligand therapy (RLT) in multiple myeloma and acute leukemia.
Six patients with heavily ...pretreated relapsed diffuse large B-cell lymphoma (3 men, 3 women; aged, 54 ± 8 y) underwent CXCR4-directed RLT in combination with conditioning chemotherapy and allogeneic stem cell transplantation. In 2 patients, radioimmunotherapy targeting CD20 or CD66 was added to enhance antilymphoma activity. Endpoints were incidence and severity of adverse events, progression-free survival, and overall survival.
RLT and additional radioimmunotherapy were well tolerated, without any acute adverse events or changes in vital signs. Successful engraftment was recorded after a median of 11 d (range, 9-13 d). Of the 4 patients who were available for follow-up (one patient died of CNS aspergillosis 29 d after RLT and another of sepsis in aplasia 34 d after RLT), CXCR4-directed RLT resulted in a partial response in two (both treated with additional radioimmunotherapy) and a mixed response in the remaining two. The response duration was rather short-lived, with a median progression-free survival of 62 d (range, 29-110 d) and a median overall survival of 76 d (range, 29-334 d).
CXCR4-directed RLT (in combination with additional radioimmunotherapy) is feasible as a conditioning regimen before allogeneic stem cell transplantation in diffuse large B-cell lymphoma.
Background
The GMP-compliant production of radiopharmaceuticals has been performed using disposable units (cassettes) with a dedicated synthesis module. To expand this “plug ‘n’ synthesize” principle ...to a broader scope of modules we developed a pressure controlled setup that offers an alternative to the usual stepper motor controlled rotary valves. The new concept was successfully applied to the synthesis of
N
-methyl-
11
Ccholine,
L
-
S
-methyl-
11
Cmethionine and
11
Cacetate.
Results
The target gas purification of cyclotron produced
11
CCO
2
and subsequent conversion to
11
CMeI was carried out on a TRACERlab Fx C Pro module. The labelling reactions were controlled with a TRACERlab Fx FE module. With the presented modular principle we were able to produce
N
-methyl-
11
Ccholine and
L
-
S
-methyl-
11
Cmethionine by loading a reaction loop with neat
N,N'
-dimethylaminoethanol (DMAE) or an ethanol/water mixture of NaOH and
L
-homocysteine (
L
-HC), respectively and a subsequent reaction with
11
CMeI. After 18 min
N
-methyl-
11
Ccholine was isolated with 52% decay corrected yield and a radiochemical purity of > 99%. For
L
-
S
-methyl-
11
Cmethionine the total reaction time was 19 min reaction, yielding 25% of pure product (> 97%). The reactor design was used as an exemplary model for the technically challenging
11
Cacetate synthesis. The disposable unit was filled with 1 mL MeMgCl (0.75 M) in tetrahydrofuran (THF) bevore
11
CCO
2
was passed through. After complete release of
11
CCO
2
the reaction mixture was quenched with water and guided through a series of ion exchangers (H
+
, Ag
+
and OH
−
). The product was retained on a strong anion exchanger, washed with water and finally extracted with saline. The product mixture was acidified and degassed to separate excess
11
CCO
2
before dispensing. Under these conditions the total reaction time was 18 ± 2 min and pure
11
Cacetate (n = 10) was isolated with a decay corrected yield of 51 ± 5%.
Conclusion
Herein, we described a novel single use unit for the synthesis of carbon-11 labelled tracers for preclinical and clinical applications of
N
-methyl-
11
Ccholine,
L
-
S
-methyl-
11
Cmethionine and
11
Cacetate.
Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed ...radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer
GaPentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies. Thirty-five patients with MM underwent
GaPentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases,
FFDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity.
GaPentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to
FFDG was available,
GaPentixafor-PET detected more lesions in 4/19 (21%) subjects,
FFDG proved superior in 7/19 (37%). In the remaining 8/19 (42%) patients, both tracers detected an equal number of lesions.
FFDG-PET positivity correlated with
GaPentixafor-PET positivity (p=0.018).
GaPentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma.
The human sodium iodide symporter (hNIS) has been the most important target in nuclear medicine regarding thyroid-related diseases. Although hNIS-expression can also be determined in extra-thyroidal ...tumors, imaging hNIS with positron emission tomography has not been exploited clinically.
Here, we evaluated the accumulation of the novel hNIS-substrate 18Ftetrafluoroborate (18FTFB) in the endogenously hNIS-expressing breast cancer cell line MCF-7 after an improved radiosynthesis and pharmacological stimulation.
18FTFB was prepared under mild reaction conditions (40°C, 25 min) and its uptake properties were investigated in MCF-7 cells pretreated with a combination of all-trans retinoic acid plus methasone-derivatives and compared to the clinically established tracers 131Iiodide and 99mTcpertechnetate. Specificity of the tracer accumulation was assessed by inhibition experiments using NaBF4, KSO3F, KI and KIO3.
18FTFB was obtained with a radiochemical yield of 24.0 ± 6.6 % (n = 17) within 40 min after high pressure liquid chromatography-separation and with 26.8 ± 6.2 % (n = 13) within 45 min after adapting the procedure on a synthesis module using higher starting activities (> 10 GBq). After pharmacological treatment, a 4-fold increase in hNIS-expression on the MCF-7 cell surface was achieved, resulting in a significantly higher 18FTFB uptake into the cells (up to 58-fold) as compared to control experiments. Inhibition studies using various NIS-substrates confirmed the specificity of 18FTFB for hNIS.
18FTFB was shown to be a promising hNIS-substrate in our model using the human MCF-7 breast cancer cell line mandating in vivo evaluations in xenografted studies and in patients.
In PET imaging, the different types of radiotracers and accumulations, as well as the diversity of disease patterns, make the analysis of molecular imaging data acquired
challenging. Here, we ...evaluate and validate a semi-automated MRI template-based data analysis tool that allows preclinical PET images to be aligned to a self-created PET template. Based on the user-defined volume-of-interest (VOI), image data can then be evaluated using three different semi-quantitative parameters: normalized activity, standardized uptake value, and uptake ratio.
The nuclear medicine Data Processing Analysis tool (NU_DPA) was implemented in Matlab. Testing and validation of the tool was performed using two types of radiotracers in different kinds of stroke-related brain diseases in rat models. The radiotracers used are 2-
Ffluoro-2-deoxyglucose (
FFDG), a metabolic tracer with symmetrical distribution in brain, and
GaGa-Fucoidan, a target-selective radioligand specifically binding to p-selectin. After manual image import, the NU_DPA tool automatically creates an averaged PET template out of the acquired PET images, to which all PET images are then aligned onto. The added MRI template-based information, resized to the lower PET resolution, defines the VOI and also allows a precise subdivision of the VOI into individual sub-regions. The aligned PET images can then be evaluated semi-quantitatively for all regions defined in the MRI atlas. In addition, a statistical analysis and evaluation of the semi-quantitative parameters can then be performed in the NU_DPA tool.
Using ischemic stroke data in Wistar rats as an example, the statistical analysis of the tool should be demonstrated. In this
FFDG-PET experiment, three different experimental states were compared: healthy control state, ischemic stroke without electrical stimulation, ischemic stroke with electrical stimulation. Thereby, statistical data evaluation using the NU_DPA tool showed that the glucose metabolism in a photothrombotic lesion can be influenced by electrical stimulation.
Our NU_DPA tool allows a very flexible data evaluation of small animal PET data
including statistical data evaluation. Using the radiotracers
FFDG and
GaGa-Fucoidan, it was shown that the semi-automatic MRI-template based data analysis of the NU_DPA tool is potentially suitable for both metabolic radiotracers as well as target-selective radiotracers.
Little is known about changes in brain metabolism following SAH, possibly leading towards secondary brain damage. Despite sustained progress in the last decade, analysis of in vivo acquired data ...still remains challenging. The present interdisciplinary study uses a semi-automated data analysis tool analyzing imaging data independently from the administrated radiotracer. The uptake of 2-
FFluoro-2-deoxy-glucose (
FFDG) was evaluated in different brain regions in 14 male Sprague-Dawley rats, randomized into two groups: (1) SAH induced by the endovascular filament model and (2) sham operated controls. Serial
FFDG-PET measurements were carried out. Quantitative image analysis was performed by uptake ratio using a self-developed MRI-template based data analysis tool. SAH animals showed significantly higher
FFDG accumulation in gray matter, neocortex and olfactory system as compared to animals of the sham group, while white matter and basal forebrain region showed significant reduced tracer accumulation in SAH animals. All significant metabolic changes were visualized from 3 h, over 24 h (day 1), day 4 and day 7 following SAH/sham operation. This
FFDG-PET study provides important insights into glucose metabolism alterations following SAH-for the first time in different brain regions and up to day 7 during course of disease.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objective
In subjects with idiopathic Parkinson’s disease (PD) the functional state of the locus coeruleus and the subtle derangements in the finely tuned dopamine–noradrenaline interplay are largely ...unknown. The PET ligand (
S,S
)-
11
C-
O
-methylreboxetine (C-11 MRB) has been described to reliably bind noradrenaline transporters but long scanning protocols might hamper its use, especially in patients with PD. We aimed to assess the feasibility of reducing C-11 MRB scans to 30 min.
Methods
Ten patients with idiopathic PD underwent dynamic C-11 MRB PET (120 min duration) and brain magnetic resonance imaging. Model-based (i.e., simplified and multilinear reference tissue model 2) non-displaceable binding potentials (BP) of selected brain regions were analyzed for a 90 min scan protocol and compared with BP derived from static 30-min data with different starting times (30, 40, 50 and 60 min) after C-11 MRB injection. Intraclass correlation coefficient and linear regression analysis were used to explore the association between BP of different scan durations. Spearman’s
ρ
served to describe the correlation of BP with demographic and clinical parameters.
Results
With respect to kinetic models, BP
50–80
and BP
60–90
showed the best correlation in several brain areas (
R
2
range 0.95–98;
p
< 0.001). The thalamus showed the highest BP on average. No correlation between BP, clinical and demographic characteristics was observed.
Conclusions
An acquisition time of 30 min, starting 50 or 60 min after C-11 MRB injection, allows a reliable estimation of noradrenaline transporter binding values in Parkinsonian people. A short acquisition time can significantly reduce the discomfort of Parkinsonian patients and facilitate PET studies, especially in the medication-off-state.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Chemokine receptor CXCR4 is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging of small cell lung cancer ...(SCLC) with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine ligand 68GaPentixafor. 10 patients with primarily diagnosed (n=3) or pre-treated (n=7) SCLC (n=9) or large cell neuroendocrine carcinoma of the lung (LCNEC, n=1) underwent 68GaPentixafor-PET/CT. 2-18Ffluoro-2-deoxy-D-glucose (18FFDG, n=6) and/or somatostatin receptor (SSTR)-directed PET/CT with 68GaDOTATOC (n=5) and immunohistochemistry (n=10) served as standards of reference. CXCR4-PET was positive in 8/10 patients and revealed more lesions with significantly higher tumor-to-background ratios than SSTR-PET. Two patients who were positive on 18FFDG-PET were missed by CXCR4-PET, in the remainder 68GaPentixafor detected an equal (n=2) or higher (n=2) number of lesions. CXCR4 expression of tumor lesions could be confirmed by immunohistochemistry. Non-invasive imaging of CXCR4 expression in SCLC is feasible. 68GaPentixafor as a novel PET tracer might serve as readout for confirmation of CXCR4 expression as prerequisite for potential CXCR4-directed treatment including receptor-radio(drug)peptide therapy.
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