Clinical Translation and First In-Human Use of [⁴⁴Sc]Sc-PSMA-617 for PET Imaging of Metastasized Castrate-Resistant Prostate Cancer

Abstract

Background: Various trivalent radiometals are well suited for labeling of DOTA-conjugated variants of Glu-ureido-based prostate-specific membrane antigen (PSMA) inhibitors. The DOTA-conjugate PSMA-617 has proven high potential in PSMA radioligand therapy (PSMA-RLT) of prostate cancer as well as PET imaging when labeled with lutetium-177 and gallium-68 respectively. Considering the relatively short physical half-life of gallium-68 this positron emitter precludes prolonged acquisition periods, as required for pre-therapeutic dosimetry or intraoperative applications. In this context, the positron emitter scandium-44 is an attractive alternative for PET imaging. We report the synthesis of [44Sc]Sc-PSMA-617 as radiopharmaceutical with generator produced scandium-44, its in vitro characterization and clinical translation as part of a first in-human study.Methods: Scandium-44 was obtained from a 44Ti/44Sc radionuclide generator. PSMA-617 was labeled with 142.4±12.7 MBq of scandium-44 in analogy to [68Ga]Ga-PSMA-617 and evaluated in vitro and in cell studies using PSMA+ LNCaP cells. A first-in-human investigation was subsequently carried out in a cohort of 4 patients (mean age 70±1.8 a) registered for [177Lu]Lu-PSMA-617 therapy. 50.5±9.3 MBq (40 µg, 38.4 nmol) [44Sc]Sc-PSMA-617 were applied via intravenous injection (i.v.), respectively. A Siemens Biograph 2 PET/CT system was used to acquire initial dynamic PET data (30 min) of abdomen in list mode followed by static PET/CT data (skull to mid-thigh) at 45 min, 2 and 18 h post-injection (p.i.). For quantitative analysis, dynamic images were reconstructed as 6 data sets of 300 s each. The noise ratio was measured in liver, lung and an additional region outside the body. SUV values in different organs and lesions were measured and compared to [68Ga]Ga-PSMA-11 data of the same patients. Residence times and organ absorbed doses were calculated using OLINDA/EXM software.Results: Quantitative radiochemical yields of ≥98 % were achieved using 18 nmol of PSMA-617 after 20 min at 95 °C with apparent molar activity of 6.69±0.78 MBq/nmol. Following purification, >99 % radiochemical purity was obtained. [44Sc]Sc-PSMA-617 showed high stability (>95 %) in serum for 24 h. The binding affinity and internalization fraction were determined in PSMA+ LNCaP cells (IC50 = 4.72±0.7 nM and internalization fraction: 15.78±2.14 % IA/106 LNCaP cells) and compared to [68Ga]Ga-PSMA-11 (12.0±2.8 nM and 9.47±2.56 % IA/106 LNCaP cells). Physiological tracer uptake was observed in kidneys, liver, spleen, small intestine, urinary bladder, and salivary glands and pathological uptake in both soft and skeletal metastases. SUV values were significantly lower in the kidneys (14.0) compared to [68Ga]Ga-PSMA-11 OET (30.5). All other measured SUV values did not show a statistically significant difference. Tumor to liver ratios were found to lie between 1.9 and 8.3 for [68Ga]Ga-PSMA-11 and between 2.5 and 8.8 for [44Sc]Sc-PSMA-617 after 120 min. For [44Sc]Sc-PSMA-617 the ratios were higher and no statistically sig...

Preparation of the alpha‐emitting prostate‐specific membrane antigen targeted radioligand [212Pb]Pb‐NG001 for prostate cancer

“…An in vitro binding study of [ 212 Pb]Pb‐NG001 and [ 212 Pb]Pb‐PSMA‐617 to C4‐2 cells yielded k d values of 22.0 and 11.1 nM, respectively (Figure S4), which are in agreement with other studies that have examined the binding of PSMA ligands to PSMA‐positive cells . Gourni et al showed that [ 11 In]In‐PSMA‐617 to LNCaP cells yielded a k d of 5.4 nM .…”

“…42,43 Figure S4), which are in agreement with other studies that have examined the binding of PSMA ligands to PSMA-positive cells. [44][45][46] Gourni et al showed that [ 11 In]In-PSMA-617 to LNCaP cells yielded a k d of 5.4 nM. 44 Umbricht et al reported that [ 177 Lu]Lu-PSMA-617, [ 44 Sc]Sc-PSMA-617 and [ 68 Ga] Ga-PSMA-617 to PC-3 PIP cells gave the k d values of 39, 33 and 72 nM, respectively.…”

Dual‐time‐point 64Cu‐PSMA‐617‐PET/CT in patients suffering from prostate cancer

“…Eppard et al investigated in a first in human study the PET tracer 44 Sc‐PSMA‐617 in patients with progressive, multiple metastases of PCa. They demonstrated the feasibility of imaging PCa tissue with an excellent image quality even 18 hours post injection allowing therapeutic dosimetric assessment prior to 177 Lu‐PSMA therapy as recently shown by Khawar et al…”

Radiometals for imaging and theranostics, current production, and future perspectives

“…44 Sc obtained in this manner was labelled to DOTATOC and, subsequently, applied to a patient for the first time . More recently, generator‐produced 44 Sc was used to prepare 44 Sc‐PSMA‐617 and injected into prostate cancer patients …”

“…79 More recently, generator-produced 44 Sc was used to prepare 44 Sc-PSMA-617 and injected into prostate cancer patients. 84 As an alternative, the production of 44 Sc was proposed using natural calcium at a cyclotron using the nat Ca(p, n) 44 Sc nuclear reaction. 85 While acceptable yields of 44 Sc were obtained after 1-hour irradiation with protons, radioisotopic impurities such as 44m Sc (T 1/2 = 58.6 h), 47 Sc (T 1/2 = 3.35 d), and 48 Sc (T 1/2 = 43.7 h) were also present in the final product.…”