First-in-Human PET/CT Imaging of Metastatic Neuroendocrine Neoplasms with Cyclotron-Produced 44 Sc-DOTATOC: A Proof-of-Concept Study

Abstract

⁴⁴Sc is a promising positron emission tomography (PET) radionuclide (T_1/2 = 4.04 hours, E_β+average = 632 keV) and can be made available, using a cyclotron production route, in substantial quantities as a highly pure product. Herein, the authors report on a first-in-human PET/CT study using ⁴⁴Sc-DOTATOC prepared with cyclotron-produced ⁴⁴Sc. The production of ⁴⁴Sc was carried out through the ⁴⁴Ca(p,n)⁴⁴Sc nuclear reaction at Paul Scherrer Institut, Switzerland. After separation, ⁴⁴Sc was shipped to Zentralklinik Bad Berka, Germany, where radiolabeling was performed, yielding radiochemically pure ⁴⁴Sc-DOTATOC. Two patients, currently followed up after peptide receptor radionuclide therapy of metastatic neuroendocrine neoplasms, participated in this proof-of-concept study. Blood sampling was performed before and after application of ⁴⁴Sc-DOTATOC. PET/CT acquisitions, performed at different time points after injection of ⁴⁴Sc-DOTATOC, allowed detection of even very small lesions on delayed scans. No clinical adverse effects were observed and the laboratory hematological, renal, and hepatic profiles remained unchanged. In this study, cyclotron-produced ⁴⁴Sc was used in the clinic for the first time. It is attractive for theranostic application with ¹⁷⁷Lu, ⁹⁰Y, or ⁴⁷Sc as therapeutic counterparts. ⁴⁴Sc-based radiopharmaceuticals will be of particular value for PET facilities without radiopharmacy, to which they can be shipped from a centralized production site.

Introduction

In recent years, ⁴⁴Sc has been proposed as a novel radionuclide for positron emission tomography (PET).^1,2 The physical properties of ⁴⁴Sc (T_1/2 = 3.97 hours—recently determined as T_1/2 = 4.04 hours³; E_β+average = 632 keV; I = 94.3%) are attractive to use this radionuclide for diagnostic imaging purposes, dosimetry, and monitoring therapy response.² As a trivalent metal, with similarities to lanthanides and rare earth elements, the chemical properties of ⁴⁴Sc enable stable coordination with a DOTA chelator.⁴ This allows the use of targeting ligands, such as somatostatin analogs (e.g., DOTATOC), which are subsequently employed for therapeutic purposes using ¹⁷⁷Lu or ⁹⁰Y. Moreover, in combination with the therapeutic match, ⁴⁷Sc (T_1/2 = 3.35 days, E_β-average = 162 keV, E_γ = 159 keV, I = 68%), one of the first truly theranostic radionuclide pairs could be clinically established in the near future.⁵ ⁴⁷Sc can be efficiently produced at high-power electron linear accelerators, generating Bremsstrahlung as proposed previously.^6,7 It is proposed that clinically significant activities can be produced in the ⁴⁸Ti(γ,p)⁴⁷Sc or ⁴⁸Ca(γ,n)⁴⁷Ca \documentclass{aastex}\usepackage{amsbsy}\usepackage{amsfonts}\usepackage{amssymb}\usepackage{bm}\usepackage{mathrsfs}\usepackage{pifont}\usepackage{stmaryrd}\usepackage{textcomp}\usepackage{portland, xspace}\usepackage{amsmath, amsxtra}\usepackage{upgreek}\pagestyle{empty}\DeclareMathSizes{10}{9}{7}{6}\begin{document}$$\mathop \to \limits^{{\beta ^ - }}$$ \end{document} ⁴⁷Sc nuclear reactions.

These characteristics give ⁴⁴Sc a unique potential for clinical PET application and have encouraged several research groups to perform proof-of-concept studies in preclinical settings with a number of tumor-targeted biomolecules. There is, however, only a single report of a clinical application of ⁴⁴Sc in a patient to date, in which ⁴⁴Sc was obtained from a ⁴⁴Ti/⁴⁴Sc generator.¹

In preclinical studies, there are a number of peptide-based ligands (e.g., somatostatin,^8
–10 bombesin,¹¹ and arginine-glycine-aspartic acid (RGD) analogs¹²) and other small-molecular-weight targeting agents (e.g., puromycin,¹³ folate,¹⁴ and prostate specific membrane antigen (PSMA) ligands¹⁵), as well as antibodies (cetuximab¹⁶), which were used for labeling with ⁴⁴Sc and subsequently investigated with regard to complex stability, determination of tissue distribution profiles, and tumor targeting in mice, including preclinical PET imaging. The most important findings underlined the superiority of DOTA over NOTA, NODAGA, and DTPA for stable coordination of ⁴⁴Sc and the similar in vitro/in vivo behavior of ⁴⁴Sc- and ¹⁷⁷Lu-labeled compounds in mice.^4,10,14,15 On the other hand, ⁴⁴Sc- and ⁶⁸Ga-labeled DOTA conjugates showed slightly different in vitro and in vivo characteristics in some cases, which can be attributed to the different coordination chemistry of the two metals.^8,10,11,15

The preclinical PET image quality was convincing and allowed excellent visualization of tumors, as well as healthy organs and tissues in which the ⁴⁴Sc-labeled conjugates accumulated.^{2,10,12

–16} To compare the image resolution that can be obtained with ⁴⁴Sc and other PET nuclides, phantom studies were recently performed with a preclinical PET scanner.¹⁷ It was revealed that the resolution of ⁴⁴Sc was superior to that of ⁶⁸Ga, but inferior when compared with ⁶⁴Cu and ⁸⁹Zr, an assessment in good agreement with the β⁺-energy of these PET nuclides. For clinical purposes, it is thus expected—and confirmed by the first clinical PET scan with ⁴⁴Sc¹—that the image resolution will be similar to what can be achieved with ⁶⁸Ga-based PET.

In view of a routine ⁴⁴Sc clinical application, the question of availability of this novel radionuclide has to be addressed. In this regard, production of ⁴⁴Sc at a cyclotron, by irradiating natural or enriched Ca targets, was previously proposed with the ^nat/44Ca(p,n)⁴⁴Sc nuclear reaction.^18,19 Over the last few years, substantial quantities of activity were produced through this method at Paul Scherrer Institut (PSI), Switzerland.² A method for the separation of ⁴⁴Sc from ⁴⁴Ca target material was developed at PSI and recently optimized. The excellent quality of the resulting ⁴⁴Sc was shown by high radionuclidic (<1% ^44mSc) and chemical purity, enabling the performance of several preclinical studies, in which tumor-targeting ligands were labeled with ⁴⁴Sc for subsequent in vitro and in vivo application.^10,14 This production method has, therefore, been considered as superior in terms of yield, cost, and feasibility over the use of a ⁴⁴Ti/⁴⁴Sc generator, developed by Rösch et al.^1,20

Given the promising decay properties and resolution capability using PET, ⁴⁴Sc has the potential to be used as an alternative to the short-lived ⁶⁸Ga (T_1/2 = 68 minutes) for PET imaging of neuroendocrine neoplasms. ⁴⁴Sc may be advantageous with regard to the half-life, as it opens the possibility of a centralized production of ⁴⁴Sc-labeled peptides and their shipment over several hundred kilometers to hospitals with PET centers that do not have a radiopharmacy on site. This may be of particular interest in countries where cyclotrons are not densely distributed, as is the case in the United States and several countries in Asia and Africa.

In this proof-of-concept study, the authors report on the first-in-human cases of PET/CT imaging, using DOTATOC labeled with cyclotron-produced ⁴⁴Sc, performed at the Theranostics Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik Bad Berka (ZBB), Germany. The aim of this study was to demonstrate the proposed concept of using cyclotron-produced ⁴⁴Sc in a clinical setting. In this regard, the authors set out to investigate the potential of ⁴⁴Sc-DOTATOC for the management of neuroendocrine neoplasms by demonstrating the physiological and pathological tissue uptake in these patients. Two male patients, previously receiving peptide receptor radionuclide therapy (PRRT) for the treatment of metastatic, pancreatic neuroendocrine neoplasms, underwent post-therapeutic restaging of the disease using PET/CT performed at several time points after administration of ⁴⁴Sc-DOTATOC.

Experimental

Production and separation of ⁴⁴Sc

⁴⁴Sc was produced by the ⁴⁴Ca(p,n)⁴⁴Sc nuclear reaction at Injector 2 cyclotron facility at PSI in Switzerland, as previously reported.^2,14 The 72 MeV proton beam was degraded (with niobium) to ∼11 MeV for the irradiation of targets at a beam current of 50 μA over a period of 90 minutes. The separation of the produced ⁴⁴Sc from the target material was carried out by chromatographic methods using non-branched N,N,N′,N′-tetra-n-octyldiglycolamide (DGA) extraction resin and strong cation exchange (SCX) resin to provide ⁴⁴Sc at a high quality and quantity, as previously reported.² The separated ⁴⁴Sc was shipped over 600 km to ZBB in Germany.

Radiolabeling of DOTATOC

Radiolabeling of the somatostatin analog DOTA⁰,Tyr³-octreotide (DOTATOC), was performed in the radiopharmacy at ZBB. Ammonium acetate buffer (0.8 M, pH 5.0) was freshly prepared using ammonium acetate dissolved in ultrapure water (Merck Darmstadt) and concentrated HCl. Radiolabeling was performed by mixing the ⁴⁴ScCl₃ solution (361 MBq, 700 μL) with ammonium acetate buffer (700 μL) and a stock solution of DOTATOC dissolved in ultrapure water (500 μL, corresponding to 250 μg DOTATOC). The reaction mixture was incubated at 91°C for 30 minutes, followed by cooling down to room temperature and neutralization of the solution by addition of sodium phosphate buffer (3 mL, 1 M, pH 7.2). After sterile filtration of the resulting solution, quality control of the radiolabeled product was performed according to the guidelines applied for ⁶⁸Ga-labeled somatostatin analogs.²¹ Radiochemical purity was determined using thin layered chromatography (TLC) and high performance liquid chromatography (HPLC). The final solution was checked with regard to the pH value, sterility, and endotoxins.

Ethical and regulatory issues

⁴⁴Sc-DOTATOC was administered in compliance with the German Medicinal Products Act (section 13, subsection 2b) and the 1964 Declaration of Helsinki. An institutional review board (European Neuroendocrine Tumor Society-certified tumor board) approved the study and both patients signed a substantial written informed consent before the investigation, which was performed in accordance with the regulations of the German Federal Agency for Radiation Protection.²² Additionally, before commencement of PRRT, written informed consent forms were signed by the patients for the purpose of collection and storage of their data in the institutional databank and national registry, the anonymized evaluation, and publication of these data.

Patient selection and characteristics

Two male patients were selected for PET/CT investigations using ⁴⁴Sc-DOTATOC for restaging after five and three cycles of ¹⁷⁷Lu- or ⁹⁰Y-based PRRT at ZBB, respectively. The patient characteristics are presented in Table 1. Patient 1 was 70 years old and suffering from well-differentiated, nonfunctional neuroendocrine neoplasm of the pancreatic tail with hepatic and lymph node metastases. At initial diagnosis, the disease was at stage IIIb. The PET/CT study reported herein was performed for restaging of the disease 6.5 years after his fifth PRRT. Patient 2 was 63 years old and suffered from a well-differentiated, functional neuroendocrine neoplasm of the pancreas head, initial WHO stage IIIb, with bilobar liver and paraaortic lymph node metastases. The PET/CT study reported herein was performed for restaging 27 months after his third PRRT.

Table 1.

Characteristics of Patient 1 and Patient 2

Characteristics	Patient 1	Patient 2
Age, years	70	63
Gender	Male	Male
Cancer type	Well-differentiated nonfunctional neuroendocrine neoplasm	Well-differentiated functional neuroendocrine neoplasm
Primary tumor	Pancreatic tail	Pancreatic head
Metastases	Liver and lymph nodes	Liver and lymph nodes
Stage of the disease (at initial diagnosis)	IIIb	IIIb
Karnofsky index (at the time of this study)	100%	100%
Previous PET scan	⁶⁸Ga-DOTATOC 12 months ago	⁶⁸Ga-DOTATOC 9 months ago
Radionuclide therapy	Five cycles of PRRT	Three cycles of PRRT
Time since last PRRT	78 Months	27 Months
Relevant previous surgery	Pancreatic tail resection with splenectomy	Pancreatic head resection with regional and mesenteric lymphadenectomy

PET, positron emission tomography; PRRT, peptide receptor radionuclide therapy.

PET/CT imaging and reconstruction parameters

PET/CT imaging was performed using a Biograph mCT Flow 64 scanner from Siemens Medical Solutions AG. Whole-body PET/CT scans were acquired in the supine position from vertex to feet at various time intervals. The PET scans were acquired using Speed 10 in flow motion. The reconstruction was performed using recon TrueX+ToF software with 3 iterations and 21 subsets decayed, applying decay correction for ⁴⁴Sc. The images were prepared using a Gaussian filter (4 mm at full width half maximum (FWHM)) and a matrix size of 200. The computed tomography (CT) scans were acquired at 100 kV and at pitch of 1.5. CareDose4D was applied using 0.5-second gantry rotation time, 5 mm slice thickness, and a matrix size of 512 × 512.

PET/CT imaging using ⁴⁴Sc-DOTATOC

The preparation of the patients included blood sampling for laboratory analysis, the morning before PET imaging, as part of the routine restaging procedure. To accelerate renal excretion of the radiotracer, furosemide (20 mg) was administered intravenously 30 minutes before the administration of ⁴⁴Sc-DOTATOC, followed by adequate oral hydration (0.75–1.0 L) with bottled drinking water. The patients received an intravenous bolus injection of 78 MBq (Patient 1) and 96 MBq (Patient 2) ⁴⁴Sc-DOTATOC, respectively. Eight sets of PET/CT scans were acquired with each patient. The time points of image acquisition for Patient 1 and Patient 2 are given in Table 2. Low-dose CT was performed for attenuation correction after oral administration of Mucofalk™ (1 L), a negative intestinal contrast agent.

Table 2.

Time Points of PET/CT Acquisition After Injection of ⁴⁴ Sc-DOTATOC

Time of acquisition ^a	Patient 1	Patient 2
Early (minutes)	0	0
	8	10
	25	25
Standard (minutes)	75	60
Moderately delayed (minutes)	150	130
	240	240
Delayed (hours)	15.5	16
	23.5	23

The indicated times refer to the time after injection of ⁴⁴Sc-DOTATOC.

Data (image) analysis

The PET/CT images obtained with ⁴⁴Sc-DOTATOC were interpreted by two physicians (one board-certified nuclear medicine physician and one board-certified radiologist, each with over 10 years of experience in reporting PET/CT studies with somatostatin analogues) independently. A qualitative and semiquantitative evaluation of the scans was performed by analyzing the somatostatin-avid lesions on the transverse, coronal, and sagittal sections. Standardized uptake values (SUV_max) were obtained by drawing circular regions of interest around each somatostatin-avid lesion, which were automatically adapted (40% isocontour) to a three-dimensional volume of interest (VOI), with the software provided by the vendor. The quantitative assessment of somatostatin-avid lesions was obtained exclusively from the transverse sections. Tumor-to-background ratios were calculated using SUV_max for the target lesions and SUV_mean for the normal background organs and tissues (right gluteus muscle, liver, right kidney, and spleen) based on a reasonably large VOI drawn over a homogeneous region. Patient 1 had a previous splenectomy, thus, tumor-to-spleen ratios were not determined.

As part of the routine clinical practice of restaging patients with neuroendocrine neoplasms being treated or followed up at ZBB, the PET/CT images obtained with ⁴⁴Sc-DOTATOC were compared with those of the previous PET/CT performed with ⁶⁸Ga-DOTATOC. The final written reports of the concurrent ultrasound (US), magnetic resonance imaging (MRI), and CT (bone window) studies documented by the radiologist were also taken into consideration for disease restaging.

Results

Production of ⁴⁴Sc and synthesis of ⁴⁴Sc-DOTATOC

Due to logistical issues, the target irradiation and chemical separation took place in the early morning hours, with 2 GBq of radionuclidically pure ⁴⁴Sc being made available for shipment to ZBB. The transport left PSI ∼1 hour later to arrive in Bad Berka a further 8 hours later, which corresponded to a total decay of two and a half half-lives. The labeling of DOTATOC was performed immediately upon arrival of the ⁴⁴Sc in the radiopharmacy at ZBB to obtain a specific activity of ∼1.4 MBq/μg peptide. The quality control of the ⁴⁴Sc-labeled product revealed a radiochemical purity of >99% based on TLC and HPLC methods. After addition of sodium phosphate buffer, the final pH of the injection solution was 6.2. Sterility and absence of endotoxins were confirmed by sterility test and limulus amebocyte lysate (LAL) test.

Pathological uptake

The PET/CT images obtained after administration of ⁴⁴Sc-DOTATOC demonstrated excellent uptake of the radiopeptide in lesions of both patients (Fig. 1). The best image quality was achieved at 4 hours after administration of ⁴⁴Sc-DOTATOC (Fig. 2).

FIG. 1.

Whole-body PET scans presented as MIP of (A) Patient 1 and (B) Patient 2 at 4 hours after injection of ⁴⁴Sc-DOTATOC (arrows indicate the lesions). Bl, urinary bladder; I, injection site; Ki, kidney; MIP, maximal intensity projections; PET, positron emission tomography; Sp, spleen; U, urine contamination.

FIG. 2.

PET/CT images (transverse sections) obtained with Patient 1 at different time points after injection of ⁴⁴Sc-DOTATOC.

In Patient 1, the scans performed with ⁴⁴Sc-DOTATOC allowed identification of a new target lesion in the dorsal aspect of segment VII of the liver in comparison with the previous PET/CT images obtained with ⁶⁸Ga-DOTATOC (Fig. 3A, B). It was coregistered as a lesion with 12 mm diameter on the concurrent MRI (Fig. 3C). As a consequence, the patient was restaged as having progressive disease. Another cycle of PRRT, however, was not indicated due to an insignificant increase in overall tumor burden. The PET/CT scan, performed with ⁶⁸Ga-DOTATOC for restaging 6 months later, demonstrated stable disease (Fig. 3D). The images allowed detection of the lesion in the dorsal aspect of segment VII of the liver, which was previously seen on the PET/CT scan performed with ⁴⁴Sc-DOTATOC (Fig. 3C).

FIG. 3.

Comparison of serial images of the transverse section of liver, representing the lesion in segment VII (green arrow), obtained by PET/CT imaging of Patient 1 using somatostatin analogs for restaging after the third cycle of PRRT (PRRT-3). (A) At 18 months after PRRT-3, the lesion was not detected on PET/CT image obtained with ⁶⁸Ga-DOTATOC; (B) at 27 months after PRRT-3, the lesion was detected using ⁴⁴Sc-DOTATOC; (C) a concurrent MRI performed within 24 hours of the PET/CT scan obtained with ⁴⁴Sc-DOTATOC coregistered the lesion seen on the PET/CT image; (D) at 36 months after PRRT-3, the lesion was detected on PET/CT images obtained with ⁶⁸Ga-DOTATOC. MRI, magnetic resonance imaging; PRRT, peptide receptor radionuclide therapy.

In Patient 2, the PET/CT images obtained with ⁴⁴Sc-DOTATOC demonstrated progressive disease, with best image quality seen at 4 hours after injection (Fig. 4).

FIG. 4.

PET/CT images (transverse sections) obtained with Patient 2 at different time points after injection of ⁴⁴Sc-DOTATOC.

In comparison with the PET/CT scan performed 9 months earlier with ⁶⁸Ga-DOTATOC, a small new lesion in the apicolateral aspect of segment VIII of the liver was detected with ⁴⁴Sc-DOTATOC PET/CT (Fig. 5A, B). This lesion was not seen on the concurrent MR and US images obtained within 24 hours after the PET scan (Fig. 5C). In this patient, PRRT was not performed due to the clinically insignificant increase in tumor burden. A follow-up PET/CT performed with ⁶⁸Ga-DOTATOC for restaging 9 months later, however, enabled detection of this lesion in apicolateral segment VIII of the liver, which was previously seen on PET images obtained with ⁴⁴Sc-DOTATOC (Fig. 5D).

FIG. 5.

Comparison of serial images of the transverse section of liver, representing the lesion in segment VIII (green arrow), obtained by PET/CT imaging of Patient 2 using somatostatin analogs. (A) Nine months before the ⁴⁴Sc-based PET/CT scan, the lesion was not detected on the image obtained with ⁶⁸Ga-DOTATOC PET/CT; (B) the lesion was detected on PET/CT images performed with ⁴⁴Sc-DOTATOC, but (C) it was not seen on a concurrent MRI performed within 24 hours of ⁴⁴Sc-based PET/CT scan; (D) 9 months later, the lesion was detected on PET/CT images obtained with ⁶⁸Ga-DOTATOC.

Physiological uptake of ⁴⁴Sc-DOTATOC

Early PET/CT images demonstrated uptake of ⁴⁴Sc-DOTATOC in the normal blood pool, including the heart and blood vessels. Mild, but decreasing, uptake of the radiopeptide was observed as background activity in the normal tissue throughout the image series. Moderate accumulation of radioactivity was visualized in the liver of both patients as well as in the spleen (Patient 2). Uptake and retention of radioactivity in the kidneys, ureters, and the urinary bladder were a consequence of renal excretion of ⁴⁴Sc-DOTATOC. It is interesting to note that there was no significant uptake of ⁴⁴Sc-DOTATOC in the pituitary, parotid, and salivary glands, as well as the thyroid and the intestines.

Tumor-to-background ratios

Tumor-to-background ratios were determined for both patients based on SUV_max of the target lesion compared with SUV_mean of physiological tissue, including gluteus muscle, liver, and kidney; as well as the spleen for Patient 2 only, measured over a reasonably large area. Increasing tumor-to-background values were observed over the first 4 hours after injection of ⁴⁴Sc-DOTATOC (Fig. 6A, C). At later time points of image acquisition (15 to 24 hours p.i.), the tumor-to-background ratios decreased (Fig. 6B, D). These findings correlated with the visual assessment of acquired images, with the best image quality seen at about 4 hours after injection of ⁴⁴Sc-DOTATOC. The relatively high tumor-to-gluteus muscle ratio indicated lower accumulation of radioactivity in the soft tissue compared with the uptake in tumor tissue. The tumor-to-liver ratios were high between 3 and 4 hours after injection, representing the most adequate time period for detection of liver metastases. The tumor-to-kidney ratios remained relatively low, however, without significant variations over time, suggesting constant accumulation of radiopeptide in the kidneys, followed by persistent elimination through urine for the entire duration of investigation in this study. In Patient 2, the tumor-to-spleen ratios remained relatively low with only marginal increase during a 1–4-hour period after injection, which suggests a higher residence time of ⁴⁴Sc-DOTATOC within the spleen.

FIG. 6.

(A, B) Patient 1: TBR based on SUV_max values obtained in tumor and nontumor tissue, including right gluteus muscle, liver, and kidneys after injection of ⁴⁴Sc-DOTATOC; (C, D) Patient 2: TBRs based on SUV_max values in tumor and nontumor tissue, including right gluteus muscle, liver, kidneys, and spleen after injection of ⁴⁴Sc-DOTATOC. Graphs (A, C) demonstrate TBRs of the first 4 hours after injection of ⁴⁴Sc-DOTATOC, while (B, D) show the TBRs over the whole period of investigation up to 24 hours. SUV, standardized uptake values; TBR, tumor-to-background ratio.

Clinical safety of ⁴⁴Sc-DOTATOC

The imaging procedure was well tolerated by both patients. No clinical adverse effects manifested by symptoms such as nausea, emesis, rash, erythema, pruritus, fever, etc. were observed or reported by either patient during, immediately after, or at follow-up checks of the patients after administration of ⁴⁴Sc-DOTATOC. Laboratory analyses, indicative for hematological, renal, and hepatic functions, remained unchanged relative to the administration of ⁴⁴Sc-DOTATOC (Table 3). According to the Common Terminology Criteria for Adverse Events (CTCAE v4.03), there were no significant changes in the relevant blood test values representing the hematological, renal, and hepatic functions at 6 months (Patient 1) and at 9 months (Patient 2), respectively. None of the laboratory values investigated during follow-up blood tests, performed after the PET/CT study with ⁴⁴Sc-DOTATOC, were significantly altered.

Table 3.

Laboratory Parameters of the Patients Before and After ⁴⁴ Sc-DOTATOC Administration

			Patient 1		Patient 2
Parameters	Normal range	Units	Before	After	Before	After
Hemoglobin	8.6–12.1	mM	9.6	9.5	7.4	8.4
Leukocytes	4.3–10	Gpt/L	5.6	4.6	6.1	6.0
Thrombocytes	150–400	Gpt/L	363	356	198	221
Urea	3–9.2	mM	4.0	5.5	5.3	4.4
Creatinine	62–106	μM	59	65.3	88	88.2
eGFR (MDRD)	>60	mL/min/1.73 m²	>60	>60	>60	>60
ALT	<0.83	μmol/s/L	0.38	0.38	0.37	0.45
AST	<0.85	μmol/s/L	0.36	0.28	0.4	0.44
GGT	0.17–1.19	μmol/s/L	0.44	0.43	0.33	1.27

Before = 2 hours before the PET/CT scan performed with ⁴⁴Sc-DOTATOC; After = at the time of the next study for restaging.

ALT, alanine transaminase; AST, aspartate transaminase; eGFR, estimated glomerular filtration rate; GGT, gamma-glutamyl transpeptidase; MDRD, modification of diet in renal disease.

Discussion

In this proof-of-concept study, the authors were able to demonstrate, for the first time, the application of cyclotron-produced ⁴⁴Sc in a clinical setting by using it with DOTATOC for restaging of neuroendocrine neoplasms in two male patients. The production of ⁴⁴Sc at the research cyclotron at PSI allowed separation of sufficient quantities of activity to be shipped over a distance of about 600 km from PSI (Switzerland) to Bad Berka (Germany). This implies that, when produced centrally at a medical cyclotron, ⁴⁴Sc doses for several patients could be delivered to distant PET imaging centers over several hundred kilometers. Cyclotron production of ⁴⁴Sc would, thus, be regarded as a more feasible option for routine application of ⁴⁴Sc-based radiopharmaceuticals compared with the ⁴⁴Ti/⁴⁴Sc generator-based production,^1,20 which provides only small activities in larger volumes.

The procedure of radiolabeling DOTATOC with ⁴⁴Sc was comparable with the method using ⁶⁸Ga, without the need of development of a new labeling technique. It has to be mentioned, however, that a relatively high amount of peptide was used for labeling, yielding a low specific activity of ⁴⁴Sc-DOTATOC (∼1.4 MBq/μg) and, as a result, a peptide amount of >55 μg was injected into the patients. In future clinical applications, it is intended to increase the specific activity of ⁴⁴Sc-DOTATOC to reduce the amount of injected peptide to <50 μg, as is commonly performed with ⁶⁸Ga-labeled somatostatin analogs.^23,24

In the present study, distinct uptake of ⁴⁴Sc-DOTATOC was observed in pathological lesions soon after injection (Figs. 2 and 4). The accumulation of ⁴⁴Sc-DOTATOC increased over time, resulting in very high tumor-to-background ratios and producing PET images of excellent quality. This was particularly evident at later time points — such as the images taken 4 hours after injection of ⁴⁴Sc-DOTATOC—when the activity was cleared from normal organs and tissues, but retained in somatostatin receptor-expressing lesions (Fig. 1).

Comparison of the ⁴⁴Sc-based PET images with those obtained with ⁶⁸Ga-DOTATOC demonstrated that there was no visually significant uptake of ⁴⁴Sc-DOTATOC in the pituitary and salivary glands, or in the intestines. This should be considered advantageous with regard to detection of small lesions, particularly in the bowel, such as carcinoma of unknown primary of the small bowel.²⁵ Dosimetric calculations have not yet been performed due to insufficient data for statistical significance, but are planned for the future, particularly in comparison with the biodistribution and dosimetry data obtained by PET imaging with ⁶⁸Ga-based DOTA-peptides.^26,27 For this purpose, a direct comparison of PET images using ⁶⁸Ga- and ⁴⁴Sc-labeled DOTATOC will be necessary within a short time interval.

In this study, visual evaluation of the acquired images indicated a relatively prolonged and higher renal uptake of activity on the delayed PET images, when compared with other organs and tissues. This was also reflected by the relatively low tumor-to-kidney ratios. Due to the longer half-life of ⁴⁴Sc, when compared with ⁶⁸Ga, the residence time of ⁴⁴Sc-DOTATOC in malignant lesions, as well as in the kidneys and spleen, was increased compared with the short-lived ⁶⁸Ga-DOTATOC. The coemission of high-energy gamma-rays (E_γ = 1157 keV, I = 99.9%) may be considered as a possible drawback for clinical application of ⁴⁴Sc with regard to the mean and total absorbed renal and spleen doses. Further clinical PET studies using ⁴⁴Sc-DOTATOC are scheduled to be performed in additional patients, enabling the calculation of the mean and total absorbed dose delivered to the tumor, as well as normal organs, tissues, and whole body. The application of ⁴⁴Sc-DOTATOC in this study was determined to be safe for human use, as there were no significant changes observed in any of the relevant laboratory parameters representing the hematological, renal, and hepatic functions of these patients following the administration of ⁴⁴Sc-DOTATOC (Table 3).

⁴⁴Sc-DOTATOC may be used either as a stand-alone imaging agent or, more importantly, as a diagnostic match to ¹⁷⁷Lu- and ⁹⁰Y-labeled DOTATOC, which are clinically established for the treatment of neuroendocrine neoplasms and other somatostatin receptor-expressing tumors.^28,29 Based on the coordination chemistry of Sc, metal complexes of Sc resemble more closely those of ¹⁷⁷Lu and ⁹⁰Y, making the use of ⁴⁴Sc-DOTATOC even more attractive compared with ⁶⁸Ga-labeled radiopharmaceuticals, which may have a different tissue distribution due to different coordination of ⁶⁸Ga using DOTA.^10,30 It remains to be mentioned that, in the future, it is very likely that ⁴⁴Sc will be used in tandem with the currently-investigated therapeutic counterpart ⁴⁷Sc, presenting one of the most intriguing examples of matched radiometals for theranostic application.

Conclusion

⁴⁴Sc-DOTATOC exhibited favorable properties for PET/CT imaging, as demonstrated by successful restaging of patients with metastatic pancreatic neuroendocrine neoplasms. Further studies with ⁴⁴Sc are envisaged, with focus on the dosimetry data and direct comparison with ⁶⁸Ga-based radiopharmaceuticals. Based on the results obtained in this study, it is believed that ⁴⁴Sc has significant clinical potential for PET/CT imaging, and importantly, as a diagnostic match to ¹⁷⁷Lu, ⁹⁰Y, and ⁴⁷Sc for theranostic application.

Footnotes

Acknowledgments

The authors thank Dr. Maruta Bunka, Katharina A. Domnanich, Walter Hirzel, and Alexander Sommerhalder for technical assistance at PSI. They express their gratitude to Mostafa Shahinfar, MD, the physicists, and the nursing staff, as well as the nuclear medicine technologists of the Theranostics Center for Molecular Radiotherapy and Molecular Imaging for patient management at ZBB. The study was financially supported by the Swiss National Science Foundation (grants CR23I2_156852 and IZLIZ3_156800).

Disclosure Statement

No competing financial interests exist.

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First-in-Human PET/CT Imaging of Metastatic Neuroendocrine Neoplasms with Cyclotron-Produced 44 Sc-DOTATOC: A Proof-of-Concept Study

Abstract

Introduction

Experimental

Production and separation of 44Sc

Radiolabeling of DOTATOC

Ethical and regulatory issues

Patient selection and characteristics

PET/CT imaging and reconstruction parameters

PET/CT imaging using 44Sc-DOTATOC

Data (image) analysis

Results

Production of 44Sc and synthesis of 44Sc-DOTATOC

Pathological uptake

Physiological uptake of 44Sc-DOTATOC

Tumor-to-background ratios

Clinical safety of 44Sc-DOTATOC

Discussion

Conclusion

Footnotes

Acknowledgments

Disclosure Statement

References

Production and separation of ⁴⁴Sc

PET/CT imaging using ⁴⁴Sc-DOTATOC

Production of ⁴⁴Sc and synthesis of ⁴⁴Sc-DOTATOC

Physiological uptake of ⁴⁴Sc-DOTATOC

Clinical safety of ⁴⁴Sc-DOTATOC