<sup>99m</sup>Tc-Labeled Small-Molecule Inhibitors of Prostate-Specific Membrane Antigen: Pharmacokinetics and Biodistribution Studies in Healthy Subjects and Patients with Metastatic Prostate Cancer

Vallabhajosula, Shankar; Nikolopoulou, Anastasia; Babich, John W.; Osborne, Joseph R.; Tagawa, Scott T.; Lipai, Irina; Solnes, Lilja B.; Maresca, Kevin P.; Armor, Thomas; Joyal, John L.; Crummet, Robert; Stubbs, James B.; Goldsmith, Stanley J.

doi:10.2967/jnumed.114.140426

Cited by 130 publications

(99 citation statements)

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“…Preoperative SPECT imaging was primarily performed to confirm sufficient tracer uptake in all suspect lesions previously identified via 68 Ga-HBED-CC-PSMA PET and thus to ensure their detectability during RGS. Surprisingly, however, the quality of planar and SPECT images obtained with 99m Tc-PSMA-I&S compares well to images obtained with alternative highly promising PSMA-targeted SPECT imaging agents such as 99m Tc-MIP-1404 ( 99m Tc-trofolastat) (8). Although the latter had displayed fundamentally different pharmacokinetics in LNCaP xenograft-bearing nude mice, that is, fast background clearance and slightly increased tumor accumulation (36), as well as substantially lower plasma protein binding (32%) (34), suitable imaging contrast in PCa patients was obtained only at time points of 4 h or more after injection because of considerable hepatic and intestinal tracer accumulation (8).…”

Section: Discussionmentioning

confidence: 99%

“…With respect to clinical diagnostic imaging, the field was pioneered by small urea-based tracers such as 99m Tc-MIP-1404 and 99m Tc-MIP-1405 for SPECT (7,8) and by 68 Ga-HBED-CC-Ahx-KuE ( 68 Ga-HBED-CC-PSMA) (9)(10)(11) or the 18 F-labeled analogs 18 F-DCFBC (12,13) and 18 F-DCFPyl (14,15) for PET. Their use for PET/CT or PET/MRI hybrid imaging has been shown to allow detection and characterization of primary and recurrent metastatic PCa, even at low prostate-specific antigen levels, with higher sensitivity, specificity, and accuracy than conventional imaging methods (16)(17)(18).…”

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confidence: 99%

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Preclinical Evaluation and First Patient Application of^99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer

et al. 2016

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Initial studies in patients have demonstrated the suitability of 111 In-PSMA-I&T ( 111 In-DOTAGA-(3-iodo-y)-f-k-Sub(KuE)) (PSMA is prostatespecific 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 99m Tc-labeling chemistry. Two PSMA-I&T-derived inhibitors with all-L-serine-(MAS 3 ) and all-D-serine-(mas 3 ) chelating moieties were evaluated in parallel, and a kit procedure for routine 99m Tc labeling was developed. Methods: PSMA affinities (IC 50 ) and internalization kinetics of 99m Tc-MAS 3 -y-nal-k (Sub-KuE) and 99m Tc-mas 3 -y-nal-k(Sub-KuE) ( 99m Tc-PSMA-I&S for imaging and surgery) were determined using LNCaP cells and ( 125 I-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 99m Tc-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 99m Tc-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 99m Tc-MAS 3 -y-nal-k(Sub-KuE) and 99m Tc-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, 99m Tc-PSMA-I&S was selected for further in vivo evaluation. Compared with 111 In-PSMA-I&T, 99m Tc-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 99m Tc-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 99m Tc-PSMA-I&S uptake in all suspect lesions identified in previous 68 Ga-HBED-CC-Ahx-KuE ( 68 Ga-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, 99m Tc-PSMA-I&S represents a cost-effective, readily available alternative to 111 In-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 99m Tc-PSMA-I&S as a SPECT imaging agent.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Preclinical Evaluation and First Patient Application of^99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer

et al. 2016

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“…Only a few studies have investigated the use of SPECT agents in recurrent PC. An initial study of 99m Tc-MIP-1404 in 6 healthy men and 6 patients with radiographic evidence of metastatic PC showed favorable biodistribution, identified most bone metastases (compared with bone scintigraphy), and detected soft-tissue PC lesions, including subcentimeter LNs (88). Subsequently, in an evaluation of 99m Tc-MIP-1404 in 60 patients, the detection rates at PSA levels of greater than 2 ng/mL and less than or equal to 2 ng/mL were 91.4% and 40.0%, respectively (89).…”

Section: Psma Ligand Imaging Biochemical Recurrencementioning

confidence: 99%

Prostate-Specific Membrane Antigen Ligands for Imaging and Therapy

et al. 2017

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The prostate-specific membrane antigen (PSMA) is highly expressed on most prostate cancer (PC) cells. Therefore, the targeting of PSMA has become increasingly important over the last decade. Glu-ureabased PSMA ligands used for both imaging and radioligand therapy are the mainstays of the current success. For PET imaging, both 68 Gaand 18 F-labeled agents have been successfully translated to clinical applications. Mainly retrospective cohort studies have shown a high value in the setting of biochemical recurrence, with high detection rates even in the presence of low prostate-specific antigen levels. Preliminary data indicated that radioguided surgery with PSMA ligands may help to further improve patient outcomes because it facilitates the removal of small tumor deposits that are otherwise difficult to detect. For primary PC, PSMA ligand PET imaging has been shown to be superior to cross-sectional imaging for the detection of metastatic lymph nodes. In addition, it promises to also provide intraprostatic tumor localization, especially when used in combination with multiparametric MRI. Increasing numbers of studies have reported considerable changes in management resulting from PSMA ligand PET imaging for both biochemical recurrence and primary disease. The use of 177 Lu-PSMA-based radioligand therapy has demonstrated a reasonable response, mainly as defined by a prostate-specific antigen response of more than 50%, comparable to other recently introduced agents. Especially given the high level of safety of 177 Lu-PSMA radioligand therapy, with only minimal grade 3 and 4 toxicities reported so far, it has the potential to expand options for metastatic castrationresistant PC. This review is intended to provide a comprehensive overview of the current literature on low-molecular-weight PSMA ligands for both PET imaging and therapeutic approaches, with a focus on agents that have been clinically adopted.

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“…1), into the clinical setting in 2010 (34,45). Although both 99m Tc agents are based on the glutamateurea amino acid core and have similar PSMA binding affinities (34), significantly different pharmacokinetic parameters were observed in human studies; these were most likely due to modest structural differences affecting hydrophobicity and protein binding (46). In patients with metastatic PCa, localization of 99m Tc agents (MIP-1404 and MIP-1405) to lesions in bone and soft tissue correlated with radiologic evidence of metastatic disease identified by bone scanning (46).…”

Section: Psma Ligand Spect Imagingmentioning

confidence: 99%

The Rise of PSMA Ligands for Diagnosis and Therapy of Prostate Cancer

et al. 2016

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^99mTc-Labeled Small-Molecule Inhibitors of Prostate-Specific Membrane Antigen: Pharmacokinetics and Biodistribution Studies in Healthy Subjects and Patients with Metastatic Prostate Cancer

Cited by 130 publications

References 24 publications

Preclinical Evaluation and First Patient Application of^99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer

Preclinical Evaluation and First Patient Application of^99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer

Prostate-Specific Membrane Antigen Ligands for Imaging and Therapy

The Rise of PSMA Ligands for Diagnosis and Therapy of Prostate Cancer

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99mTc-Labeled Small-Molecule Inhibitors of Prostate-Specific Membrane Antigen: Pharmacokinetics and Biodistribution Studies in Healthy Subjects and Patients with Metastatic Prostate Cancer

Cited by 130 publications

References 24 publications

Preclinical Evaluation and First Patient Application of99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer

Preclinical Evaluation and First Patient Application of99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer

Prostate-Specific Membrane Antigen Ligands for Imaging and Therapy

The Rise of PSMA Ligands for Diagnosis and Therapy of Prostate Cancer

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Product

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^99mTc-Labeled Small-Molecule Inhibitors of Prostate-Specific Membrane Antigen: Pharmacokinetics and Biodistribution Studies in Healthy Subjects and Patients with Metastatic Prostate Cancer

Preclinical Evaluation and First Patient Application of^99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer

Preclinical Evaluation and First Patient Application of^99mTc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer