Ali Afshar-Oromieh

[68Ga]Gallium-labelled PSMA ligand as superior PET tracer for the diagnosis of prostate cancer: comparison with 18F-FECH

Prostate-specific membrane antigen (PSMA) is a cell surface protein, which is expressed at higher levels in prostate cancer compared to other tissues. This protein provides a promising target for specific imaging and therapy due to its transmembrane location and internalization after ligand binding [1]. PSMA is also expressed in the neovasculature of many solid tumours [2, 3]. Recently procedures have been developed to label PSMA with Ga and I for positron emission tomography (PET) imaging [4, 5]. We present for the first time PET/CT images obtained with Ga-labelled HBED-CC conjugate of the PSMA-specific pharmacophore Glu-NH-CO-NH-Lys (Ga-PSMA). The images were compared with [F]FECH PET/CT of the same patient. The 67-year-old patient had undergone previous radiotherapy of the prostate due to carcinoma and had received androgen therapy since 2002. The patient presented with a continuous increase of PSA values (from 1 ng/ml in 2002 to 7.4 ng/ml in May 2011) and was referred to our department for further analysis using PET/CT. F-FECH PET/CT was unable to detect any lesions. However, Ga-PSMA PET/CT did show a lesion adjacent to the urinary bladder compatible with tumour relapse (figure). Our initial experience with Ga-PSMA PET/CT strongly suggests that this novel method can detect prostate carcinoma relapses and metastases with significantly improved contrast compared to F-FECH PET/CT. Further clinical studies should confirm this observation and determine if PSMA PET/CT can replace F-FECH PET/CT in the diagnosis of prostate carcinoma.

Novel Preclinical and Radiopharmaceutical Aspects of [68Ga]Ga-PSMA-HBED-CC: A New PET Tracer for Imaging of Prostate Cancer

The detection of prostate cancer lesions by PET imaging of the prostate-specific membrane antigen (PSMA) has gained highest clinical impact during the last years. 68Ga-labelled Glu-urea-Lys(Ahx)-HBED-CC ([68Ga]Ga-PSMA-HBED-CC) represents a successful novel PSMA inhibitor radiotracer which has recently demonstrated its suitability in individual first-in-man studies. The radiometal chelator HBED-CC used in this molecule represents a rather rarely used acyclic complexing agent with chemical characteristics favourably influencing the biological functionality of the PSMA inhibitor. The simple replacement of HBED-CC by the prominent radiometal chelator DOTA was shown to dramatically reduce the in vivo imaging quality of the respective 68Ga-labelled PSMA-targeted tracer proving that HBED-CC contributes intrinsically to the PSMA binding of the Glu-urea-Lys(Ahx) pharmacophore. Owing to the obvious growing clinical impact, this work aims to reflect the properties of HBED-CC as acyclic radiometal chelator and presents novel preclinical data and relevant aspects of the radiopharmaceutical production process of [68Ga]Ga-PSMA-HBED-CC.

Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer

Despite many advances in the past years, the treatment of metastatic prostate cancer still remains challenging. In recent years, prostate-specific membrane antigen (PSMA) inhibitors were intensively studied to develop low-molecular-weight ligands for imaging prostate cancer lesions by PET or SPECT. However, the endoradiotherapeutic use of these compounds requires optimization with regard to the radionuclide-chelating agent and the linker moiety between chelator and pharmacophore, which influence the overall pharmacokinetic properties of the resulting radioligand. In an effort to realize both detection and optimal treatment of prostate cancer, a tailor-made novel naphthyl-containing DOTA-conjugated PSMA inhibitor has been developed. Methods: The peptidomimetic structure was synthesized by solid-phase peptide chemistry and characterized using reversed-phase high-performance liquid chromatography and matrix-assisted laser desorption/ionization mass spectrometry. Subsequent 67/68Ga and 177Lu labeling resulted in radiochemical yields of greater than 97% or greater than 99%, respectively. Competitive binding and internalization experiments were performed using the PSMA-positive LNCaP cell line. The in vivo biodistribution and dynamic small-animal PET imaging studies were investigated in BALB/c nu/nu mice bearing LNCaP xenografts. Results: The chemically modified PSMA inhibitor PSMA-617 demonstrated high radiolytic stability for at least 72 h. A high inhibition potency (equilibrium dissociation constant [Ki] = 2.34 ± 2.94 nM on LNCaP; Ki = 0.37 ± 0.21 nM enzymatically determined) and highly efficient internalization into LNCaP cells were demonstrated. The small-animal PET measurements showed high tumor-to-background contrasts as early as 1 h after injection. Organ distribution revealed specific uptake in LNCaP tumors and in the kidneys 1 h after injection. With regard to therapeutic use, the compound exhibited a rapid clearance from the kidneys from 113.3 ± 24.4 at 1 h to 2.13 ± 1.36 percentage injected dose per gram at 24 h. The favorable pharmacokinetics of the molecule led to tumor-to-background ratios of 1,058 (tumor to blood) and 529 (tumor to muscle), respectively, 24 h after injection. Conclusion: The tailor-made DOTA-conjugated PSMA inhibitor PSMA-617 presented here is sustainably refined and advanced with respect to its tumor-targeting and pharmacokinetic properties by systematic chemical modification of the linker region. Therefore, this radiotracer is suitable for a first-in-human theranostic application and may help to improve the clinical management of prostate cancer in the future.

[177Lu]Lutetium-labelled PSMA ligand-induced remission in a patient with metastatic prostate cancer

The prostate-specific membrane antigen (PSMA) shows intense overexpression in the majority of prostate cancers (PCa) [1]. A Glu-urea-Lys motif has been found to bind with high affinity to the catalytic domain of PSMA [2]. Following conjugation to the chelator HBED-CC, a Ga-labelled PSMA ligand (Ga-DKFZ-11) has been derived as a novel PET tracer [3]. Since PSMA is internalized after binding of a ligand [4], it is also an excellent target for systemic radionuclide therapy. Consequently, a I-labelled PSMA ligand (I-MIP-1095) demonstrated favourable tumour-targeting properties and promising antitumour efficacy [5]. However, clinical application of I causes a high radiation burden and is hampered by complex regulations in most countries. Therefore, Lu is considered to be preferable for targeted radionuclide therapy. The novel theranostic drug Lu-DKFZ-617 is a DOTA derivative of the Glu-urea-Lys motif. The chelator is conjugated via an aromatic linker that further improves tumour accumulation while simultaneously reducing kidney uptake. The image presented here shows a patient with metastatic PCa. PSMA PET/CT (a) demonstrates a tumour phenotype with strong PSMA expression. The patient was treated with a cumulative activity of 7.4 GBq Lu-DKFZ-617 (b, c). Restaging with PSMA PET/CT (d) reveals a striking radiological response. In addition the PSA level decreased from 38.0 to 4.6 ng/ml. Patient stratification by means of PSMA imaging and subsequent treatment with a therapeutic PSMA-targeted

Intra-individual comparison of 18F-FET and 18F-DOPA in PET imaging of recurrent brain tumors

BACKGROUND Both (18)F-fluorodihydroxyphenylalanine ((18)F-DOPA) and (18)F-fluoroethyltyrosine ((18)F-FET) have already been used successfully for imaging of brain tumors. The aim of this study was to evaluate differences between these 2 promising tracers to determine the consequences for imaging protocols and the interpretation of findings. METHODS Forty minutes of dynamic PET imaging were performed on 2 consecutive days with both (18)F-DOPA and (18)F-FET in patients with recurrent low-grade astrocytoma (n = 8) or high-grade glioblastoma (n = 8). Time-activity-curves (TACs), standardized uptake values (SUVs) and compartment modeling of both tracers were analyzed, respectively. RESULTS The TAC of DOPA-PET peaked at 8 minutes p.i. with SUV 5.23 in high-grade gliomas and 10 minutes p.i. with SUV 4.92 in low-grade gliomas. FET-PET peaked at 9 minutes p.i. with SUV 3.17 in high-grade gliomas and 40 minutes p.i. with SUV 3.24 in low-grade gliomas. Neglecting the specific uptake of DOPA into the striatum, the tumor-to-brain and tumor-to-blood ratios were higher for DOPA-PET. Kinetic modeling demonstrated a high flow constant k1 (mL/ccm/min), representing cellular internalization through AS-transporters, for DOPA in both high-grade (k1 = 0.59) and low-grade (k1 = 0.55) tumors, while lower absolute values and a relevant dependency from tumor-grading (high-grade k1 = 0.43; low-grade k1 = 0.33) were observed with FET. CONCLUSIONS DOPA-PET demonstrates superior contrast ratios for lesions outside the striatum, but SUVs do not correlate with grading. FET-PET can provide additional information on tumor grading and benefits from lower striatal uptake but presents lower contrast ratios and requires prolonged imaging if histology is not available in advance due to a more variable time-to-peak.

PET/MRI with a 68Ga-PSMA ligand for the detection of prostate cancer

Ga-labelled PSMA ligandGlu-NH-CO-NH-Lys(Ahx)-HBED-CC.A 68-year-old patient was referred to our institution for radi-ation therapy planning and exclusion of distant metastases 4-months after biopsy-proven dia gnosis of left peripheral prostatecancer(PSA18.5ng/ml,Gleason score7).Whole-bodyPET/CT1 hour after injection of 171 MBq

68Ga-PSMA-11 PET Imaging of Response to Androgen Receptor Inhibition: First Human Experience.

The purpose of this work was to evaluate the effect of androgen receptor (AR) inhibition on prostate-specific membrane antigen (PSMA) uptake imaged using 68Ga-PSMA-11 PET in a mouse xenograft model and in a patient with castration-sensitive prostate cancer. Methods: We imaged 3 groups of 4 mice bearing LNCaP-AR xenografts before and 7 d after treatment with ARN-509, orchiectomy, or control vehicle. Additionally, we imaged one patient with castration-sensitive prostate cancer before and 4 wk after treatment with androgen deprivation therapy (ADT). Uptake on pre- and posttreatment imaging was measured and compared. Results: PSMA uptake increased 1.5- to 2.0-fold in the xenograft mouse model after treatment with both orchiectomy and ARN-509 but not with vehicle. Patient imaging demonstrated a 7-fold increase in PSMA uptake after the initiation of ADT. Thirteen of 22 lesions in the imaged patient were visualized on PSMA PET only after treatment with ADT. Conclusion: Inhibition of the AR can increase PSMA expression in prostate cancer metastases and increase the number of lesions visualized using PSMA PET. The effect seen in cell and animal models can be recapitulated in humans. A better understanding of the temporal changes in PSMA expression is needed to leverage this effect for both improved diagnosis and improved therapy.

Hybrid Positron Emission Tomography–Magnetic Resonance Imaging with Gallium 68 Prostate-specific Membrane Antigen Tracer: A Next Step for Imaging of Recurrent Prostate Cancer—Preliminary Results

Modern treatment strategies substantially increased progression-free survival of prostate cancer (PCa) as well as overall outcome in patients diagnosed with localized highrisk PCa. However, some patients experience biochemical failure after definitive treatment [1]. In these cases, early detection of tumor spread into lymph nodes and bone represents a challenge for current imaging technologies. At present, positron emission tomography (PET) combined with computed tomography (CT) is the most accurate method of oncologic staging for recurrent disease [2]. Nevertheless, PET/CT has the limitation of low soft tissue contrast in the CT component. The drawbacks of PET/CT may potentially be overcome by a fully integrated, wholebody, hybrid PET–magnetic resonance imaging (MRI) system, which features increased accuracy using simultaneous acquisition of high-resolution morphologic and functional data [3,4]. Arce-Calisaya et al. [5] recently reported the potential of simultaneous PET/MRI to detect PCa in a case of recurrent disease using an C-choline tracer. Beyond standard choline-based tracers, novel PET tracers, binding to specific PCa antigens, have the potential

Comparison of 68Ga-DOTATOC-PET/CT and PET/MRI hybrid systems in patients with cranial meningioma: Initial results

BACKGROUND (68)Ga-DOTATOC-PET/CT is a well-established method for detecting and targeting the volume definition of meningiomas prior to radiotherapy. Moreover, there is evidence that this method is able to detect meningiomas with higher sensitivity than the goldstandard MRI. Since the hybrid PET/MRI scanner became available in the past few years, the next stage of development could consequently evolve by evaluating the feasibility of a hybrid PET/MRI scanner using (68)Ga-DOTATOC for detecting meningiomas. METHODS Fifteen patients received (68)Ga-DOTATOC-PET/CT (0.5 h post injection [p.i.]) followed by PET/MRI 2 hours p.i. Both investigations were analyzed separately and then compared with respect to image quality, detection of intracranial meningiomas, and radiotracer uptake values (RUVs). In addition, ratios between radiotracer uptake in meningiomas and pituitary glands were compared between both PET/CT and PET/MRI. RESULTS Overall, 33 intracranial meningiomas were detected. All were visible with high contrast in both PET/CT and PET/MRI. (68)Ga-DOTATOC-PET/MRI provided flawless image quality without artefacts. Calculated RUV in meningiomas, as well as the ratios of RUVs in meningiomas to those of pituitary glands, were higher in PET/CT. As a result, meningiomas can be distinguished from pituitary glands better in early images. CONCLUSIONS (68)Ga-DOTATOC-PET/MRI provided flawless image quality and presented an ideal combination of high sensitivity/specificity (PET) and the best possible morphological visualization of meningiomas (MRI). In addition, excellent detection of meningiomas is already possible at 0.5 hours p.i. Later images do not improve the distinction between pituitary gland and adjacent meningiomas. However, RUVs need to be carefully compared between both imaging modalities.

Comparison of 68 Ga-DOTATOC-PET/CT and PET/MRI hybrid systems in patients with cranial meningioma

BACKGROUND (68)Ga-DOTATOC-PET/CT is a well-established method for detecting and targeting the volume definition of meningiomas prior to radiotherapy. Moreover, there is evidence that this method is able to detect meningiomas with higher sensitivity than the goldstandard MRI. Since the hybrid PET/MRI scanner became available in the past few years, the next stage of development could consequently evolve by evaluating the feasibility of a hybrid PET/MRI scanner using (68)Ga-DOTATOC for detecting meningiomas. METHODS Fifteen patients received (68)Ga-DOTATOC-PET/CT (0.5 h post injection [p.i.]) followed by PET/MRI 2 hours p.i. Both investigations were analyzed separately and then compared with respect to image quality, detection of intracranial meningiomas, and radiotracer uptake values (RUVs). In addition, ratios between radiotracer uptake in meningiomas and pituitary glands were compared between both PET/CT and PET/MRI. RESULTS Overall, 33 intracranial meningiomas were detected. All were visible with high contrast in both PET/CT and PET/MRI. (68)Ga-DOTATOC-PET/MRI provided flawless image quality without artefacts. Calculated RUV in meningiomas, as well as the ratios of RUVs in meningiomas to those of pituitary glands, were higher in PET/CT. As a result, meningiomas can be distinguished from pituitary glands better in early images. CONCLUSIONS (68)Ga-DOTATOC-PET/MRI provided flawless image quality and presented an ideal combination of high sensitivity/specificity (PET) and the best possible morphological visualization of meningiomas (MRI). In addition, excellent detection of meningiomas is already possible at 0.5 hours p.i. Later images do not improve the distinction between pituitary gland and adjacent meningiomas. However, RUVs need to be carefully compared between both imaging modalities.