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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.

Heart failure remains a major source of late morbidity and mortality after myocardial infarction (MI). The temporospatial presence of activated fibroblasts in the injured myocardium predicts the quality of cardiac remodeling after MI. Therefore, monitoring of activated fibroblasts is of great interest for studying cardiac remodeling after MI. Fibroblast activation protein (FAP) expression is upregulated in activated fibroblasts. This study investigated the feasibility of imaging activated fibroblasts with a new 68 Ga-labeled FAP inhibitor (68 Ga-FAPI-04) for PET imaging of fibroblast activation in a preclinical model of MI. Methods: MI and sham-operated rats were scanned with 68 Ga-FAPI-04 PET/CT (1, 3, 6, 14, 23, and 30 d after MI) and with 18 F-FDG (3 d after MI). Dynamic 68 Ga-FAPI-04 PET and blocking studies were performed on MI rats 7 d after coronary ligation. After in vivo scans, the animals were euthanized and their hearts harvested for ex vivo analyses. Cryosections were prepared for autoradiography, hematoxylin and eosin (H&E), and immunofluorescence staining. Results: 68 Ga-FAPI-04 uptake in the injured myocardium peaked on day 6 after coronary ligation. The tracer accumulated intensely in the MI territory, as identified by decreased 18 F-FDG uptake and confirmed by PET/MR and H&E staining. Autoradiography and H&E staining of cross-sections revealed that 68 Ga-FAPI-04 accumulated mainly at the border zone of the infarcted myocardium. In contrast, there was only minimal uptake in the infarct of the blocked rats, comparable to the uptake in the remote noninfarcted myocardium (PET image-derived ratio of infarct uptake to remote uptake: 6 ± 2). Immunofluorescence staining confirmed the presence of FAP-positive myofibroblasts in the injured myocardium. Morphometric analysis of the whole-heart sections demonstrated 3-and 8-fold higher FAP-positive fibroblast density in the border zone than in the infarct center and remote area, respectively. Conclusion: 68 Ga-FAPI-04 represents a promising radiotracer for in vivo imaging of post-MI fibroblast activation. Noninvasive imaging of activated fibroblasts may have significant diagnostic and prognostic value, which could aid clinical management of patients after MI.

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