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Simultaneous quantitative imaging of two PET radiotracers via the detection of positron–electron annihilation and prompt gamma emissions

Nature Biomedical Engineering volume 7, pages 1028–1039 (2023)Cite this article

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Abstract

In conventional positron emission tomography (PET), only one radiotracer can be imaged at a time, because all PET isotopes produce the same two 511 keV annihilation photons. Here we describe an image reconstruction method for the simultaneous in vivo imaging of two PET tracers and thereby the independent quantification of two molecular signals. This method of multiplexed PET imaging leverages the 350–700 keV range to maximize the capture of 511 keV annihilation photons and prompt γ-ray emission in the same energy window, hence eliminating the need for energy discrimination during reconstruction or for signal separation beforehand. We used multiplexed PET to track, in mice with subcutaneous tumours, the biodistributions of intravenously injected [124I]I-trametinib and 2-deoxy-2-[18F]fluoro-d-glucose, [124I]I-trametinib and its nanoparticle carrier [89Zr]Zr-ferumoxytol, and the prostate-specific membrane antigen (PSMA) and infused PSMA-targeted chimaeric antigen receptor T cells after the systemic administration of [68Ga]Ga-PSMA-11 and [124I]I. Multiplexed PET provides more information depth, gives new uses to prompt γ-ray-emitting isotopes, reduces radiation burden by omitting the need for an additional computed-tomography scan and can be implemented on preclinical and clinical systems without any modifications in hardware or image acquisition software.

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Fig. 1: Overview of mPET using a pure positron and positron–gamma radionuclide pair.
Fig. 2: mPET processing workflow in comparison with traditional PET.
Fig. 3: Phantom performance of mPET on preclinical and clinical PET/CT systems.
Fig. 4: mPET of two small-molecule radiotracers for enhanced therapy monitoring.
Fig. 5: Visualizing nanoparticle delivery with mPET.
Fig. 6: Tracking CAR T-cell therapy with mPET.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. Source Data and sinograms for the phantoms in Fig. 3 are available at https://doi.org/10.5281/zenodo.8034519 while figures are available from figshare with the identifier https://doi.org/10.6084/m9.figshare.21816069.

Code availability

The mPET code consists of several modules, requiring access to additional code considered proprietary to the PET-scanner manufacturers (although for PET/CT systems such as the Siemens Inveon, it can be made available in a compiled version). In addition, the software requires hands-on training for implementation, which can be made available on reasonable request. The Monte Carlo code, MCGPU-PET, can be accessed via Github at https://github.com/DIDSR/MCGPU-PET, whereas code for reconstructing doubles and triples can also be accessed via https://github.com/jlherraiz/GFIRST. Isotope separation is determined from phantom studies performed on each scanner and isotope pair used.

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Acknowledgements

We thank D. Bauer of the Lewis Lab for their timely production of [68Ga]Ga-PSMA-11, and V. Longo and P. Zanzonico of the Small Animal Imaging Core (MSKCC) for their support maintaining the Inveon PET/CT. We also thank E. Fung and M. Du of the Citigroup Biomedical Imaging Center (Weill Cornell) for their availability and operation of the Biograph mCT clinical PET/CT and M. Conti from Siemens for their direction on how to acquire 64-bit data with the mCT. In addition, we thank E. Lage, V. Parot, S. R. Dave, S. C. Moore and the Madrid-MIT m+Vision Consortium for their help with the initial steps in the development of the mPET method. This work was supported in parts by the following grants: National Institutes of Health R01 CA215700 and R01 EB033000 (to J.G.), R01 CA220524-01A1 (to V.P.), R01 CA204924 (to V.P.), R21 CA250478 (to V.P.), S10 OD016207-01 (to P. Zanzonico, MSKCC), and P30 CA08748 (to S. M. Vickers MSKCC). A.V. is supported by The Center for Experimental Immuno-Oncology Fellowship Award (FP00001443, Memorial Sloan Kettering Cancer Center). E.C.P. is currently supported by the National Institutes of Health F32 CA268912-01. J.L.H. is currently supported by the Spanish Ministry of Science and Innovation (MCIN) (PID2021-126998OB-I00, PDC2022-133057-I00/AEI/10.13039/501100011033/ Unión Europea Next GenerationEU/PRTR). J.M.U. is currently supported by the Spanish Ministry of Science and Innovation (MCIN) (PID2021-126998OB-I00).

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Authors and Affiliations

  1. Department of Pharmacology, Weill Cornell Graduate School, New York, NY, USA

    Edwin C. Pratt & Jan Grimm

  2. Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Edwin C. Pratt, Vladimir Ponomarev & Jan Grimm

  3. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Edwin C. Pratt, Alessia Volpe, Lukas M. Carter, Nagavarakishore Pillarsetty, Vladimir Ponomarev & Jan Grimm

  4. Nuclear Physics Group, EMFTEL and IPARCOS, Complutense University of Madrid, Madrid, Spain

    Alejandro Lopez-Montes, Jose M. Udías & Joaquin L. Herraiz

  5. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA

    Alejandro Lopez-Montes

  6. Department of Cell and Developmental Biology, Weill Cornell Graduate School, New York, NY, USA

    Michael J. Crowley & Vivek Mittal

  7. Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, USA

    Vivek Mittal

  8. Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, USA

    Vivek Mittal

  9. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, USA

    Vivek Mittal

  10. Instituto de Investigación Sanitaria Hospital Clínico San Carlos, Madrid, Spain

    Jose M. Udías & Joaquin L. Herraiz

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Contributions

E.C.P., A.L.M., A.V., M.J.C. and L.M.C. conducted and planned experiments, analysed data and wrote the manuscript. V.M., N.P., V.P, J.M.U., J.G. and J.L.H. designed experiments, analysed data and wrote the manuscript.

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Correspondence to Jan Grimm or Joaquin L. Herraiz.

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Nature Biomedical Engineering thanks Huafeng Liu, Bertrand Tavitian and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 Extended mPET imaging of nanoparticle biodistribution through 96 hours.

Including data from Fig. 5 and extending through 96 hours. No change in biodistribution seen by standard reconstruction or mPET between 24 and 96 hours. %IA/CC represents percent injected activity per cubic centimetre.

Extended Data Fig. 2 Characterization of the tricistronic CAR T-cell PET-reporter system.

Gene map of PET and reporter genes for CAR T cells containing the sodium Iodide symporter (hNIS), PSMA targeting scFv (P28z), and a BLI reporter system (exCLuc) to produce the CAR-T-cell hNIS.P28z.exCLuc. b, Flow plot of PC3 cells engineered lacking PSMA. c, PSMA-positive engineered cells. d, Flow plot of CAR T cells expressing the anti-PSMA-scFv. e, In vitro activation of the BLI reporter in tricistronic CAR T cells shows functional incorporation of the genes. f, Addition of 124I to wild-type or tricistronic CAR T cells shows an increase with only tricistronic CAR T cells, with mild blocking with sodium perchlorate, confirming the specific uptake of 124I through hNIS. g, Confocal imaging of wild-type and hNIS tricistronic CAR-T cells for nuclear staining, hNIS and WGA (wheat germ agglutinin). Scale bar, 5 µm. h, In vitro cytotoxicity of PSMA targeting CAR-T cells reduces cell population in PSMA-positive co-cultures, whereas PSMA-null cells were unaffected through 48 hours by the co culture with CAR-T cells. I, In vivo delivery of CAR T cells targeting PSMA-positive tumours led to reduced tumour growth in PSMA-positive tumours, whereas PSMA-negative tumours continued to grow. In e, f, h, I, the lines denote the mean with error bars representing the s.e.m. b-d, Representative flow-cytometry contour quadrant plot to show cell-intensity characteristics. The gating scheme can be found in Supplementary Fig. 11. e, Box plot representing min and max values, with the middle line as the mean. In f, h, n = 3 technical replicates per condition. In i, n = 5 mice per arm. In e,h, the P values are significant, using a multiple-comparison unpaired t-test and assuming the same s.d. in the population. %IA/CC represents percent injected activity per cubic centimetre.

Extended Data Fig. 3 Alternative ex vivo labelling of CAR T-cells with [89Zr]Zr-Oxine and PSMA imaging with [86Y]Y-DOTA-PSMA.

[86Y]Y-DOTA-PSMA / [89Zr]Zr-oxine CAR T-cell mPET was found to have uptake of both PSMA-11 and CAR T -cell tracers in the PSMA-positive tumour (left), whereas minor to no activity was observed in both tracers for the PSMA-null tumour (right). Distribution of the [86Y]Y-DOTA-PSMA tracer can be seen in the PSMA-positive tumour, in the ocular cavity where injected, and in the bladder during excretion. [89Zr]Zr-oxine CAR T-cells were observed in the PSMA-positive tumour as well as in the liver and bone. Images were calibrated to a maximal 2.5 %IA/CC for [86Y]Y-DOTA-PSMA and 7.5 %IA/CC for [89Zr]Zr-oxine CAR T-cells. We used one mouse. %IA/CC represents percent injected activity per cubic centimetre.

Extended Data Fig. 4 mPET for developing immunoPET detection of T-cell exhaustion.

Mice bearing HKP1 lung tumours were monitored for terminal and progenitor T-cell exhaustion using antibodies against CD39 or Ly108 during disease progression. BLI of lung tumour burden was measured prior to injection, with representative CT slice in thoracic cavity showing potential branch occlusions (bright spots off alveolar bifurcation). Ly108, a marker of effector T cells, decreased with disease burden whereas CD39, a marker of severely exhausted T cells, increased, according to flow-cytometry data. mPET imaging with [89Zr]Zr-DFO-CD39 and [124I]I-Ly108 at day 7 and day 14 with three levels of tumour burden. At day 7 no discernible difference between low, medium or high tumour burden in mice is seen with either [89Zr]Zr-DFO-CD39 or [124I]I-Ly108. By day 14, BLI shows an appreciable increase in tumour burden in all mice, with tumour occlusions seen on CT. By mPET there was a general increase in [89Zr]Zr-DFO-CD39 and [124I]I-Ly108 uptake in the lungs compared to the day-7 group. Less lung uptake was visible with [124I]I-Ly108, with increasing tumour burden in the day-14 imaged mice. mPET again could separate two radiotracers in vivo and could be used with further radiotracer engineering to define T-cell exhaustion. N = 3 mice imaged per week (n = 6 total cohort), with each mouse receiving simultaneously [89Zr]Zr-DFO-CD39 and [124I]I-Ly108 by intravenous injection 48 hours prior to mPET. %IA/CC represents percent injected activity per cubic centimetre.

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Supplementary Video 1

Rotating images with combined and separated PET/CT scans from a representative mouse (from Fig. 6), windowed at 0–5% injected dose per gram for both radiotracers, to identify PSMA-positive and CAR T-cell positive tumours.

Supplementary Video 2

Rotating images analogous to those in Supplementary Video 1, calibrated to 0–30% injected dose per gram, to show the majority of the radiotracer distribution and elimination.

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Pratt, E.C., Lopez-Montes, A., Volpe, A. et al. Simultaneous quantitative imaging of two PET radiotracers via the detection of positron–electron annihilation and prompt gamma emissions. Nat. Biomed. Eng 7, 1028–1039 (2023). https://doi.org/10.1038/s41551-023-01060-y

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