Preclinical Evaluation and First Patient Application of 99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer
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Preclinical Evaluation and First Patient Application of 99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer. / Robu, Stephanie; Schottelius, Margret; Eiber, Matthias; Maurer, Tobias; Gschwend, Jürgen; Schwaiger, Markus; Wester, Hans-Jürgen.
in: J NUCL MED, Jahrgang 58, Nr. 2, 02.2017, S. 235-242.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung
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TY - JOUR
T1 - Preclinical Evaluation and First Patient Application of 99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer
AU - Robu, Stephanie
AU - Schottelius, Margret
AU - Eiber, Matthias
AU - Maurer, Tobias
AU - Gschwend, Jürgen
AU - Schwaiger, Markus
AU - Wester, Hans-Jürgen
N1 - © 2017 by the Society of Nuclear Medicine and Molecular Imaging.
PY - 2017/2
Y1 - 2017/2
N2 - Initial studies in patients have demonstrated the suitability of 111In-PSMA-I&T (111In-DOTAGA-(3-iodo-y)-f-k-Sub(KuE)) (PSMA is prostate-specific membrane antigen and I&T is imaging and therapy) for radioguided surgery (RGS) of small metastatic prostate cancer (PCa) soft-tissue lesions. To meet the clinical need for a more cost-effective alternative, the PSMA-I&T-based tracer concept was adapted to 99mTc-labeling chemistry. Two PSMA-I&T-derived inhibitors with all-L-serine- (MAS3) and all-D-serine- (mas3) chelating moieties were evaluated in parallel, and a kit procedure for routine 99mTc labeling was developed.METHODS: PSMA affinities (IC50) and internalization kinetics of 99mTc-MAS3-y-nal-k(Sub-KuE) and 99mTc-mas3-y-nal-k(Sub-KuE) (99mTc-PSMA-I&S for imaging and surgery) were determined using LNCaP cells and (125I-BA)KuE as a radioligand and reference standard. In vivo metabolite analyses and biodistribution studies were performed using CD-1 nu/nu and LNCaP tumor-bearing CB-17 severe combined immunodeficiency mice. The pharmacokinetics of 99mTc-PSMA-I&S in humans were investigated in a patient with advanced metastatic PCa via sequential planar whole-body SPECT imaging at 1, 3, 5, and 21 h after injection. Additionally, preoperative SPECT/CT (12 h after injection) and 99mTc-PSMA-I&S-supported RGS (16 h after injection) were performed in 1 PCa patient with proven iliac and inguinal lymph node metastases.RESULTS: A robust and reliable kit-labeling procedure was established, allowing the preparation of 99mTc-MAS3-y-nal-k(Sub-KuE) and 99mTc-PSMA-I&S in consistently high radiochemical yield and purity (≥98%, n > 50 preparations). Because of its improved internalization efficiency and superior in vivo stability, 99mTc-PSMA-I&S was selected for further in vivo evaluation. Compared with 111In-PSMA-I&T, 99mTc-PSMA-I&S showed delayed clearance kinetics but identical uptake in PSMA-positive tissues in the LNCaP xenograft model (1 h after injection). In exemplary PCa patients, a relatively slow whole-body clearance of 99mTc-PSMA-I&S was observed due to high plasma protein binding (94%) of the tracer. This, however, promoted efficient tracer uptake in PCa lesions over time and led to steadily increasing lesion-to-background ratios up to 21 h after injection. Preoperative SPECT/CT showed a high 99mTc-PSMA-I&S uptake in all suspect lesions identified in previous 68Ga-HBED-CC-Ahx-KuE (68Ga-HBED-CC-PSMA) PET/CT, allowing for their successful intraoperative detection and resection during first-in-human RGS.CONCLUSION: Because of a straightforward and reliable kit production, 99mTc-PSMA-I&S represents a cost-effective, readily available alternative to 111In-PSMA-I&T. Initial patient data indicate its comparable or even superior performance as a probe for PSMA-targeted RGS and also hint toward the unexpected potential of 99mTc-PSMA-I&S as a SPECT imaging agent.
AB - Initial studies in patients have demonstrated the suitability of 111In-PSMA-I&T (111In-DOTAGA-(3-iodo-y)-f-k-Sub(KuE)) (PSMA is prostate-specific membrane antigen and I&T is imaging and therapy) for radioguided surgery (RGS) of small metastatic prostate cancer (PCa) soft-tissue lesions. To meet the clinical need for a more cost-effective alternative, the PSMA-I&T-based tracer concept was adapted to 99mTc-labeling chemistry. Two PSMA-I&T-derived inhibitors with all-L-serine- (MAS3) and all-D-serine- (mas3) chelating moieties were evaluated in parallel, and a kit procedure for routine 99mTc labeling was developed.METHODS: PSMA affinities (IC50) and internalization kinetics of 99mTc-MAS3-y-nal-k(Sub-KuE) and 99mTc-mas3-y-nal-k(Sub-KuE) (99mTc-PSMA-I&S for imaging and surgery) were determined using LNCaP cells and (125I-BA)KuE as a radioligand and reference standard. In vivo metabolite analyses and biodistribution studies were performed using CD-1 nu/nu and LNCaP tumor-bearing CB-17 severe combined immunodeficiency mice. The pharmacokinetics of 99mTc-PSMA-I&S in humans were investigated in a patient with advanced metastatic PCa via sequential planar whole-body SPECT imaging at 1, 3, 5, and 21 h after injection. Additionally, preoperative SPECT/CT (12 h after injection) and 99mTc-PSMA-I&S-supported RGS (16 h after injection) were performed in 1 PCa patient with proven iliac and inguinal lymph node metastases.RESULTS: A robust and reliable kit-labeling procedure was established, allowing the preparation of 99mTc-MAS3-y-nal-k(Sub-KuE) and 99mTc-PSMA-I&S in consistently high radiochemical yield and purity (≥98%, n > 50 preparations). Because of its improved internalization efficiency and superior in vivo stability, 99mTc-PSMA-I&S was selected for further in vivo evaluation. Compared with 111In-PSMA-I&T, 99mTc-PSMA-I&S showed delayed clearance kinetics but identical uptake in PSMA-positive tissues in the LNCaP xenograft model (1 h after injection). In exemplary PCa patients, a relatively slow whole-body clearance of 99mTc-PSMA-I&S was observed due to high plasma protein binding (94%) of the tracer. This, however, promoted efficient tracer uptake in PCa lesions over time and led to steadily increasing lesion-to-background ratios up to 21 h after injection. Preoperative SPECT/CT showed a high 99mTc-PSMA-I&S uptake in all suspect lesions identified in previous 68Ga-HBED-CC-Ahx-KuE (68Ga-HBED-CC-PSMA) PET/CT, allowing for their successful intraoperative detection and resection during first-in-human RGS.CONCLUSION: Because of a straightforward and reliable kit production, 99mTc-PSMA-I&S represents a cost-effective, readily available alternative to 111In-PSMA-I&T. Initial patient data indicate its comparable or even superior performance as a probe for PSMA-targeted RGS and also hint toward the unexpected potential of 99mTc-PSMA-I&S as a SPECT imaging agent.
KW - Aged
KW - Animals
KW - Antigens, Surface
KW - Glutamate Carboxypeptidase II
KW - Humans
KW - Male
KW - Mice
KW - Mice, SCID
KW - Pilot Projects
KW - Prostatectomy
KW - Prostatic Neoplasms
KW - Radiopharmaceuticals
KW - Surgery, Computer-Assisted
KW - Technetium
KW - Tomography, Emission-Computed, Single-Photon
KW - Treatment Outcome
KW - Case Reports
KW - Journal Article
U2 - 10.2967/jnumed.116.178939
DO - 10.2967/jnumed.116.178939
M3 - SCORING: Journal article
C2 - 27635024
VL - 58
SP - 235
EP - 242
JO - J NUCL MED
JF - J NUCL MED
SN - 0161-5505
IS - 2
ER -