68Ga-PSMA-HBED-CC PET as new imaging biomarker of renal cancer

Maura Scarlattei1, Umberto Maestroni2, Donatello Gasparro3, Giorgio Baldari1, Silvia Migliari1, Antonino Sammartano1, Francesco Ziglioli2, Livia Ruffini1
  • 1 Azienda Ospedaliero-Universitaria di Parma, Unità PCa, Unità di Medicina Nucleare (Parma)
  • 2 Azienda Ospedaliero-Universitaria di Parma, Unità PCa, Unità di Urologia (Parma)
  • 3 Azienda Ospedaliero-Universitaria di Parma, Unità PCa, Unità di Oncologia (Parma)


RCC is a potentially lethal cancer with aggressive behaviour, and has a propensity for distant metastatic spread.
Up to one-third of patients with newly diagnosed RCC have metastatic diseases [1].
Furthermore,more than 30% of patients with localized disease will develop metastases after nephrectomy, and have a poor 5-year survival rate below 10% [2].
The earlier detection of metastases can offer more opportunities to act early and elicit a better therapeutic effect, especially when the metastatic lesion is confined and isolated. Conventional imaging procedures for staging and restaging of RCC patients commonly consist of computed tomography, MRI, and bone scintigraphy.
Positron emission tomography (PET)/CT is a powerful noninvasive tool used for characterizing solid tumors. Currently, clinical PET imaging for metastatic RCC is primarily obtained through metabolic imaging with Fluorodeoxyglucose (FDG)-PET/CT used for staging and assessing treatment response [3].
For the clear cell subtype (ccRCC), there is growing interest in non-FDG molecular imaging agents that may have greater sensitivity and specificity and may potentially add phenotypic information for patient/tumor-specific treatment strategies.
Prostate specific membrane antigen (PSMA) is a 750 amino acid, type II transmembrane glycoprotein that has been shown to be over-expressed in both prostate cancer cells and the vasculature of solid tumours [4].
PSMA is highly expressed in the proximal tubules of normal kidney tissues, and specifically in the neovasculature of ccRCC (75%), chromophobe (31%), oncocytoma (53%) and transitional cell carcinoma (21%) [5].
Due to the enzymatic activity of PSMA it was possible to develop specific inhibitors from which "small molecule" radiopharmaceuticals were derived. Recently methods have been developed to label PSMA ligands with 68Ga enabling PET/CT imaging to detect prostate cancer by targeting the extracellular domain of PSMA.
The most widely used PSMA-ligand for PET-imaging in Europe is a 68Ga-labelled PSMA inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC ([68Ga]-PSMA-HBED-CC).
In this study, we evaluate the diagnostic potential of [68Ga]-PSMA-HBED-CC PET/CT (PSMA-PET/CT) in restaging patients with ccRCC.

Materials and Methods

Ten patients with ccRCC were submitted to PSMA-PET/CT exam In order to verify the real staging of the disease or for inconclusive results of conventional imaging.
Synthesis of [68Ga]-PSMA-HBED-CC was performed using a fully automated module (Scintomics GRP®, Fuerstenfeldbruck, Germany) and 68Ga was obtained from a IGG100 68Ge/68Ga generator (Eckert & Ziegler, E&Z, Berlin, Germany). Our method to assess the radiochemical and chemical purity of [68Ga]-PSMA-HBED-CC was previously validated [6-7]. The mean yield of labelling reaction was 65.53% and the radiochemical purity 99.90% .
Whole body PET/CT was acquired, from vertex to medium thigh of the femur. 60 min after i.v. injection of [68Ga]PSMA-HBED-CC (150 MBq) on a hybrid scanner Discovery IQ (GE Healthcare). In all patients, a non-diagnostic CT was acquired for attenuation correction.
Tracer uptake was evaluated using spherical volumes of interest (VOIs) semi-automatically drawn on orthogonal planes. For each study maximum standardized uptake value (SUVmax) was recorded for each lesion.


PSMA-PET/CT detected multiple areas of avid tracer uptake in 7 pts with mean SUVmax 46,4 (range 21-114). PSMA-PET/CT revealed greater disease extension in comparison with CT in the same anatomic context (i.e. bone, lymphnodes). Moreover, PSMA-PET/CT detected occult metastatic lesions in 4 pts not revealed by conventional imaging in thyroid, bone, cerebellum, adrenal gland, lung.
In 1 patient PSMA-PET/CT demonstrated an unknown single brain metastic lesion that was submitted to IGRT with complete remission.


ccRCC is the most common (70–90%) and more aggressive RCC than other common histological types such as papillary and chromophobe. Increased angiogenesis by ccRCC can be utilised to potentially improve staging using PSMA-targeted imaging technologies as PET/CT. We show that PSMA-PET/CT may identify small metastatic lesions not obvious on routine imaging.
In general, clear-cell RCC metastases are depicted with high visual contrast in various anatomic sites including the lung, pleura, bone and lymph nodes.
There is growing interest in molecular imaging agents that may have greater sensitivity and specificity and may potentially add phenotypic information for the tailoring of individualized targeted-therapies.  In this context, PSMA-PET/CT has emerged as a promising, more accurate method.  The multidisciplinary context of the PCa Unit allows appropriate utilization of complex diagnostic tools as PSMA-PET/CT directly connecting disease assessment and treatment planning decisions.


In our patients, PET/CT with [68Ga]-PSMA-HBED-CC demonstrated high in vivo PSMA expression in ccRCC metastatic lesions improving diagnostic sensitivity by detection of occult lesions at the conventional imaging (thyroid, adrenal gland) and real assessment of disease burden.
Moreover, PSMA-targeted imaging may potentially be used to predict and/or assess response to systemic therapy.


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6) Eder, M.; Neels, O.; Müller, M. Novel preclinical and radiopharmaceutical aspects of [68Ga]Ga-PSMA-HBED-CC: A New PET tracer for imaging of prostate cancer Pharmaceuticals 2014, 7, 779– 796 DOI: 10.3390/ph7070779
7) Silvia Migliari, Antonino Sammartano, Maura Scarlattei, Giulio Serreli, Caterina Ghetti, Carla Cidda, Giorgio Baldari, Ornella Ortenzia, and Livia Ruffini. Development and Validation of a High-Pressure Liquid Chromatography Method for the Determination of Chemical Purity and Radiochemical Purity of a [68Ga]-Labeled Glu-Urea-Lys(Ahx)- HBED-CC (Positron Emission Tomography) Tracer. ACS Omega 2017, 2, 7120-7126