PT  - JOURNAL ARTICLE
AU  - Robu, Stephanie
AU  - Schottelius, Margret
AU  - Eiber, Matthias
AU  - Maurer, Tobias
AU  - Gschwend, Jürgen
AU  - Schwaiger, Markus
AU  - Wester, Hans-Jürgen
TI  - Preclinical Evaluation and First Patient Application of <sup>99m</sup>Tc-PSMA-I&S for SPECT Imaging and Radioguided Surgery in Prostate Cancer
AID  - 10.2967/jnumed.116.178939
DP  - 2017 Feb 01
TA  - Journal of Nuclear Medicine
PG  - 235--242
VI  - 58
IP  - 2
4099  - http://jnm.snmjournals.org/content/58/2/235.short
4100  - http://jnm.snmjournals.org/content/58/2/235.full
SO  - J Nucl Med2017 Feb 01; 58
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.