Safety and Efficacy of Para-Aminohippurate Coinfusion for Renal Protection During Peptide Receptor Radiotherapy in Patients with Neuroendocrine Tumors.

Para-aminohippurate, also known as p-aminohippuric acid (PAH), is used clinically to measure effective renal plasma flow. Preclinically, it was shown to reduce 177Lu-DOTATOC uptake in the kidneys while improving bioavailability compared with amino acid (AA) coinfusion. We report the safety and efficacy of PAH coinfusion during peptide receptor radiotherapy in patients with neuroendocrine tumors. Methods: Twelve patients with metastatic or unresectable gastroenteropancreatic neuroendocrine tumors received 177Lu-DOTATOC in 33 treatment cycles. Either 8 g of PAH or a mixture of 25 g of arginine and 25 g of lysine were coinfused. Safety was assessed by monitoring laboratory data, including hematologic and renal data, as well as electrolytes obtained before and 24 h after treatment. For radiation dosimetry, whole-body scans were performed at 1, 24, and 48 h and a SPECT/CT scan was performed at 48 h, along with blood sampling at 5 min and 0.5, 2, 4, 24, and 48 h after administration. Absorbed dose estimations for the kidneys and bone marrow were performed according to the MIRD concept. Results: In 15 treatment cycles, PAH was coinfused. No changes in mean creatinine level, glomerular filtration rate, and serum electrolytes were observed before or 24 h after treatment when using PAH protection (P ≥ 0.20), whereas serum chloride and serum phosphate increased significantly under AA (both P < 0.01). Kidney-absorbed dose coefficients were 0.60 ± 0.14 Gy/GBq with PAH and 0.53 ± 0.16 Gy/GBq with AA. Based on extrapolated cumulative kidney-absorbed doses for 4 cycles, 1 patient with PAH protection and 1 patient with AA protection in our patient group would exceed the 23-Gy conservative threshold. The bone marrow-absorbed dose coefficient was 0.012 ± 0.004 Gy/GBq with PAH and 0.012 ± 0.003 Gy/GBq with AA. Conclusion: PAH is a promising alternative to AA for renal protection during peptide receptor radiotherapy. Further research is required to systematically investigate the safety profile and radiation dosimetry at varying PAH plasma concentrations.

Evaluation of Safety and Dosimetry of 177Lu-DOTA-ZOL for Therapy of Bone Metastases.

Palliative treatment of bone metastasis using radiolabeled bisphosphonates is a well-known concept proven to be safe and effective. A new therapeutic radiopharmaceutical for bone metastasis is 177Lu-DOTA-zoledronic acid (177Lu-DOTA-ZOL). In this study, the safety and dosimetry of a single therapeutic dose of 177Lu-DOTA-ZOL were evaluated on the basis of a series of SPECT/CT images and blood samples. Methods: Nine patients with exclusive bone metastases from metastatic castration-resistant prostate cancer (mCRPC) (70.8 ± 8.4 y) and progression under conventional therapies participated in this prospective study. After receiving 5,780 ± 329 MBq 177Lu-DOTA-ZOL, patients underwent 3-dimensional whole-body SPECT/CT imaging and venous blood sampling over 7 d. Dosimetric evaluation was performed for main organs and tumor lesions. Safety was assessed by blood biomarkers. Results:177Lu-DOTA-ZOL showed fast uptake and high retention in bone lesions and fast clearance from the bloodstream in all patients. The average retention in tumor lesions was 0.02% injected activity per gram at 6 h after injection and approximately 0.01% at 170 h after injection. In this cohort, the average absorbed doses in bone tumor lesions, kidneys, red bone marrow, and bone surfaces were 4.21, 0.17, 0.36, and 1.19 Gy/GBq, respectively. The red marrow was found to be the dose-limiting organ for all patients. A median maximum tolerated injected activity of 6.0 GBq may exceed the defined threshold of 2 Gy for the red bone marrow in individual patients (4/8). Conclusion:177Lu-DOTA-ZOL is safe and has a favorable therapeutic index compared with other radiopharmaceuticals used in the treatment of osteoblastic bone metastases. Personalized dosimetry, however, should be considered to avoid severe hematotoxicity for individual patients.

A prospective intra-individual comparison of [68Ga]Ga-PSMA-11 PET/CT, [68Ga]Ga-NODAGAZOL PET/CT, and [99mTc]Tc-MDP bone scintigraphy for radionuclide imaging of prostate cancer skeletal metastases.

PURPOSE: Prostate cancer (PCa) commonly metastasizes to the bones. There are several radionuclide techniques for imaging PCa skeletal metastases. We aimed to compare the lesion detection rate of [68Ga]Ga-PSMA-11 PET/CT, [68Ga]Ga-NODAGA-zoledronate ([68Ga]Ga-NODAGAZOL) PET/CT, and [99mTc]Tc-MDP bone scan in the assessment of bone metastases in patients with advanced PCa. METHODS: We prospectively recruited two cohorts of patients (staging and re-staging cohorts) with advanced prostate cancer. The staging cohort was treatment-naïve PCa patients who showed skeletal metastases on bone scan. These patients were subsequently imaged with [68Ga]Ga-PSMA-11 PET/CT and [68Ga]Ga-NODAGAZOL PET/CT. Re-staging cohort was patients who were previously treated with PSMA-based radioligand therapy and were experiencing PSA progression. The re-staging cohort was imaged with [68Ga]Ga-PSMA-11 PET/CT and [68Ga]Ga-NODAGAZOL PET/CT. We performed a per-patient and per-lesion analysis of skeletal metastases in both cohorts and made a comparison between scan findings. RESULTS: Eighteen patients were included with a median age of 68 years (range = 48-80) and a median Gleason score of 8. There were ten patients in the staging cohort with a median PSA of 119.26 ng/mL (range = 4.63-18,948.00) and eight patients in the re-staging cohort with a median PSA of 48.56 ng/mL (range = 6.51-3175.00). In the staging cohort, skeletal metastases detected by [68Ga]Ga-PSMA-11 PET/CT, [68Ga]Ga-NODAGAZOL PET/CT, and bone scan were 322, 288, and 261, respectively, p = 0.578. In the re-staging cohort, [68Ga]Ga-PSMA-11 PET/CT and [68Ga]Ga-NODAGAZOL PET/CT detected 152 and 191 skeletal metastases, respectively, p = 0.529. In two patients with negative [68Ga]Ga-PSMA-11 PET/CT findings, [68Ga]Ga-NODAGAZOL detected one skeletal metastasis in one patient and 12 skeletal metastases in the other. CONCLUSION: In patients with advanced prostate cancer, [68Ga]Ga-PSMA-11 PET/CT may detect more lesions than [68Ga]Ga-NODAGAZOL PET/CT and [99mTc]Tc-MDP bone scan for the staging of skeletal metastases. In patients who experience PSA progression on PSMA-based radioligand therapy, [68Ga]Ga-NODAGA PET/CT is a more suitable imaging modality for the detection of skeletal lesions not expressing PSMA. In the setting of re-staging, [68Ga]Ga-NODAGAZOL PET/CT may detect more lesions than [68Ga]Ga-PSMA-11 PET/CT.

Biodistribution and dosimetry of a single dose of albumin-binding ligand [177Lu]Lu-PSMA-ALB-56 in patients with mCRPC.

INTRODUCTION: PSMA-targeted radionuclide therapy with lutetium-177 has emerged as an effective treatment option for metastatic, castration-resistant prostate cancer (mCRPC). Recently, the concept of modifying PSMA radioligands with an albumin-binding entity was demonstrated as a promising measure to increase the tumor uptake in preclinical experiments. The aim of this study was to translate the concept to a clinical setting and evaluate the safety and dosimetry of [177Lu]Lu-PSMA-ALB-56, a novel PSMA radioligand with albumin-binding properties. METHODS: Ten patients (71.8 ± 8.2 years) with mCRPC received an activity of 3360 ± 393 MBq (120-160 µg) [177Lu]Lu-PSMA-ALB-56 followed by whole-body SPECT/CT imaging over 7 days. Volumes of interest were defined on the SPECT/CT images for dosimetric evaluation for healthy tissue and tumor lesions. General safety and therapeutic efficacy were assessed by measuring blood biomarkers. RESULTS: [177Lu]Lu-PSMA-ALB-56 was well tolerated, and no severe adverse events were observed. SPECT images revealed longer circulation of [177Lu]Lu-PSMA-ALB-56 in the blood with the highest uptake in tumor lesions at 48 h post injection. Compared with published data for other therapeutic PSMA radioligands (e.g. PSMA-617 and PSMA I&T), normalized absorbed doses of [177Lu]Lu-PSMA-ALB-56 were up to 2.3-fold higher in tumor lesions (6.64 ± 6.92 Gy/GBq) and similar in salivary glands (0.87 ± 0.43 Gy/GBq). Doses to the kidneys and red marrow (2.54 ± 0.94 Gy/GBq and 0.29 ± 0.07 Gy/GBq, respectively) were increased. CONCLUSION: Our data demonstrated that the concept of albumin-binding PSMA-radioligands is feasible and leads to increased tumor doses. After further optimization of the ligand design, the therapeutic outcomes may be improved for patients with prostate cancer.

[177Lu]Lu-DOTA-ZOL bone pain palliation in patients with skeletal metastases from various cancers: efficacy and safety results.

BACKGROUND: [177Lu]Lu-DOTA-ZOL has shown promising results from the dosimetry and preclinical aspects, but data on its role in the clinical efficacy are limited. The objective of this study is to evaluate the efficacy and safety of [177Lu]Lu-DOTA-ZOL as a bone pain palliation agent in patients experiencing pain due to skeletal metastases from various cancers. METHODS: In total, 40 patients experiencing bone pain due to skeletal metastases were enrolled in this study. The patients were treated with a mean cumulative dose of 2.1 ± 0.6 GBq (1.3-2.7 GBq) [177Lu]Lu-DOTA-ZOL in a median follow-up duration of 10 months (IQR 8-14 months). The primary outcome endpoint was response assessment according to the visual analogue score (VAS). Secondary endpoints included analgesic score (AS), global pain assessment score, Eastern Cooperative Oncology Group Assessment performance status (ECOG), Karnofsky performance status, overall survival, and safety assessment by the National Cancer Institute's Common Toxicity Criteria V5.0. RESULTS: In total, 40 patients (15 males and 25 females) with a mean age of 46.6 ± 15.08 years (range 24-78 years) were treated with either 1 (N = 15) or 2 (N = 25) cycles of [177Lu]Lu-DOTA-ZOL. According to the VAS response assessment criteria, complete, partial, and minimal responses were observed in 11 (27.5%), 20 (50%), and 5 patients (12.5%), respectively with an overall response rate of 90%. Global pain assessment criteria revealed complete, partial, minimal, and no response in 2 (5%), 25 (62.5%), 9 (22.5%), and 4 (10%) patients, respectively. Twenty-eight patients died and the estimated median overall survival was 13 months (95% CI 10-14 months). A significant improvement was observed in the VAS, AS, and ECOG status when compared to baseline. None of the patients experienced grade III/IV haematological, kidney, or hepatotoxicity due to [177Lu]Lu-DOTA-ZOL therapy. CONCLUSION: [177Lu]Lu-DOTA-ZOL shows promising results and is an effective radiopharmaceutical in the treatment of bone pain due to skeletal metastases from various cancers.

Novel Radiolabeled Bisphosphonates for PET Diagnosis and Endoradiotherapy of Bone Metastases.

Bone metastases, often a consequence of breast, prostate, and lung carcinomas, are characterized by an increased bone turnover, which can be visualized by positron emission tomography (PET), as well as single-photon emission computed tomography (SPECT). Bisphosphonate complexes of 99mTc are predominantly used as SPECT tracers. In contrast to SPECT, PET offers a higher spatial resolution and, owing to the 68Ge/68Ga generator, an analog to the established 99mTc generator exists. Complexation of Ga(III) requires the use of chelators. Therefore, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), NOTA (1,4,7-triazacyclododecane-1,4,7-triacetic acid), and their derivatives, are often used. The combination of these macrocyclic chelators and bisphosphonates is currently studied worldwide. The use of DOTA offers the possibility of a therapeutic application by complexing the ß-emitter 177Lu. This overview describes the possibility of diagnosing bone metastases using [68Ga]Ga-BPAMD (68Ga-labeled (4-{[bis-(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid) as well as the successful application of [177Lu]Lu-BPAMD for therapy and the development of new diagnostic and therapeutic tools based on this structure. Improvements concerning both the chelator and the bisphosphonate structure are illustrated providing new 68Ga- and 177Lu-labeled bisphosphonates offering improved pharmacological properties.

Evaluation of bone-seeking novel radiotracer 68Ga-NO2AP-Bisphosphonate for the detection of skeletal metastases in carcinoma breast.

PURPOSE: The successful labelling of bisphosphonates (BP) with 68Ga using macrocyclic chelators such as the based triazacyclononane (NO2AP) is a step forward in the in-house availability of a novel bone-seeking PET radiopharmaceutical with dual advantage of PET/CT imaging and generator production. In this study, we compared the novel generator-based skeletal radiotracer 68Ga-1,4,7-triazacyclonone-1,4-diacetic acid (68Ga-NO2AP-BP) with sodium fluoride (18F-NaF) for the detection of skeletal metastases in breast cancer patients. In addition, dosimetric analysis of 68Ga-NO2AP-BP was performed in a subset of patients. METHODS: This was a prospective study of histopathologically proven cases of breast cancer patients who were referred for bone scintigraphy and underwent positron emission tomography/computed tomography (PET/CT) with 18F-NaF and 68Ga-NO2AP-BP within a week in random order. The scans of each patient were compared both qualitatively for image quality and quantitatively for number of lesions and SUVmax of lesions. Dosimetric analysis was performed in five patients. Their PET/CT scans were acquired at multiple time points and urine and blood samples were collected. Dosimetric calculations were performed using OLINDA/EXM 1.1 software. Statistical analysis was done using Stata 13 (StataCorp) software package. An agreement analysis regarding number of lesions detected with the two skeletal radiotracers was carried out. RESULTS: The image quality of 68Ga-NO2AP-BP PET/CT scans were comparable to that of 18F-NaF. There was no statistically significant difference in the SUVmax of lesions, normal bone and lesion to background ratio between the two skeletal radiotracers. There was good agreement in the number of lesions detected by both skeletal radiotracers. The mean whole body effective dose for 68Ga-NO2AP-BP was 0.00583 mSv/MBq and the effective dose equivalent was 0.0086 mSv/MBq. CONCLUSION: The excellent lesion detection agreement between 68Ga-NO2AP-BP and 18F-NaF favours the former as an alternative for skeletal scintigraphy in centres without an on-site cyclotron. The favourable dosimetric results and its potential to be used as a theranostic agent makes it an important generator-based skeletal radiotracer.

A DOTA based bisphosphonate with an albumin binding moiety for delayed body clearance for bone targeting.

Radiolabeled bisphosphonates are commonly used in the diagnosis and therapy of bone metastases. Blood clearance of bisphosphonates is usually fast and only 30%-50% of the injected activity is retained in the skeleton, while most of the activity is excreted by the urinary tract. A longer blood circulation may enhance accumulation of bisphosphonate compounds in bone metastases. Therefore, a chemically modified macrocyclic bisphosphonate derivative with an additional human albumin binding entity was synthesized and pharmacokinetics of its complex was evaluated. The DOTA-bisphosphonate conjugate BPAMD was compared against the novel DOTAGA-derived albumin-binding bisphosphonate DOTAGA(428-d-Lys)MBP (L1). The ligands were labeled with 68Ga(III) and were evaluated in in vitro binding studies to hydroxyapatite (HA) as well as to human serum albumin. The compounds were finally compared in in vivo PET and ex vivo organ distribution studies in small animals over 6h. Binding studies revealed a consistent affinity of both bisphosphonate tracers to HA. Small animal PET and ex vivo organ distribution studies showed longer blood retention of [68Ga]L1. [68Ga]BPAMD is initially more efficiently bound to the bone but skeletal accumulation of the modified compound and [68Ga]BPAMD equalized at 6h p.i. Ratios of femur epiphyseal plate to ordinary bone showed to be more favorable for [68Ga]L1 than for [68Ga]BPAMD due to the longer circulation time of the new tracer. Thus, the chemical modification of BPAMD toward an albumin-binding bisphosphonate, L1, resulted in a novel PET tracer which conserves advantages of both functional groups within one and the same molecule. The properties of this new diagnostic tracer are expected to be preserved in 177Lu therapeutic agent with the same ligand (a theranostic pair).

Comprehensive Quality Control of the ITG 68Ge/68Ga Generator and Synthesis of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC for Clinical Imaging.

UNLABELLED: A good-manufacturing-practices (GMP) (68)Ge/(68)Ga generator that uses modified dodecyl-3,4,5-trihydroxybenzoate hydrophobically bound to a octadecyl silica resin (C-18) as an adsorbent has been developed that allows for dilute HCl (0.05N) to efficiently elute metal-impurity-free (68)Ga(3+) ready for peptide labeling. We characterized the performance of this generator system over a year in conjunction with the production of (68)Ga-labeled DOTATOC and Glu-NH-CO-NH-Lys(Ahx)-HBED-CC (PSMA-HBED-CC) intended for clinical studies and established protocols for batch release. METHODS: A 2,040-MBq self-shielded (68)Ge/(68)Ga generator provided metal-free (68)GaCl3 ready for peptide labeling in the fluidic labeling module after elution with 4 mL of 0.05N HCl. The compact system was readily housed in a laminar flow cabinet allowing an ISO class-5 environment. (68)Ga labeling of peptides using GMP kits was performed in 15-20 min, and the total production time was 45-50 min. Batch release quality control specifications were established to meet investigational new drug submission and institutional review board approval standards. RESULTS: Over a period of 12 mo, (68)Ga elution yields from the generator averaged 80% (range, 72.0%-95.1%), and (68)Ge breakthrough was less than 0.006%, initially decreasing with time to 0.001% (expressed as percentage of (68)Ge activity present in the generator at the time of elution), a unique characteristic of this generator. The radiochemical purity of both (68)Ga-DOTATOC and (68)Ga-PSMA-HBED-CC determined by high-performance liquid chromatography analysis was greater than 98%, with a minimum specific activity of 12.6 and 42 GBq/µmol, respectively. The radionuclidic ((68)Ge) impurity was 0.00001% or less (under the detection limit). Final sterile, pyrogen-free formulation was provided in physiologic saline with 5%-7% ethanol. CONCLUSION: The GMP-certified (68)Ge/(68)Ga generator system was studied for a year. The generator system is contained within the fluidic labeling module, and it is compact, self-shielded, and easy to operate using simple manual techniques. The system provides radiolabeled peptides with high (>98%) radiochemical purity and greater than 80% radiochemical yield. The (68)Ge levels in the final drug products were under the detection limits at all times. (68)Ga-DOTATOC and (68)Ga-PSMA-HBED-CC investigational radiopharmaceuticals are currently being studied clinically under investigational new drug (IND) applications submitted to the U.S. Food and Drug Administration.

(177)Lu-labelled macrocyclic bisphosphonates for targeting bone metastasis in cancer treatment.

BACKGROUND: Metastatic bone lesion is a common syndrome of many cancer diseases in an advanced state. The major symptom is severe pain, spinal cord compression, and pathological fracture, associated with an obvious morbidity. Common treatments including systemic application of bisphosphonate drugs aim on pain reduction and on improving the quality of life of the patient. Particularly, patients with multiple metastatic lesions benefit from bone-targeting therapeutic radiopharmaceuticals. Agents utilizing beta-emitting radionuclides in routine clinical praxis are, for example, [(89)Sr]SrCl2 and [(153)Sm]Sm-EDTMP. No-carrier-added (n.c.a.) (177)Lu is remarkably suitable for an application in this scope. METHODS: Five 1,4,7,10-tetraazacyclododecane N,N',N'',N''-tetra-acetic acid (DOTA)- and DO2A-based bisphosphonates, including monomeric and dimeric structures and one 1,4,7-triazacyclononane-1,4-diacetic acid (NO2A) derivative, were synthesized and labelled with n.c.a. (177)Lu. Radio-TLC and high-performance liquid chromatography (HPLC) methods were successfully established for determining radiochemical yields and for quality control. Their binding to hydroxyapatite was measured in vitro. Ex vivo biodistribution experiments and dynamic in vivo single photon computed tomography (SPECT)/CT measurements were performed in healthy rats for 5 min and 1 h periods. Data on %ID/g or standard uptake value (SUV) for femur, blood, and soft-tissue organs were analyzed and compared with [(177)Lu]citrate. RESULTS: Radiolabelling yields for [(177)Lu]Lu-DOTA and [(177)Lu]Lu-NO2A monomeric bisphosphonate complexes were >98 % within 15 min. The dimeric macrocyclic bisphosphonates showed a decelerated labelling kinetics, reaching a plateau after 30 min of 60 to 90 % radiolabelling yields. All (177)Lu-bisphosphonate complexes showed exclusive accumulation in the skeleton. Blood clearance and renal elimination were fast. SUV data (all for 1 h p.i.) in the femur ranged from 3.34 to 5.67. The bone/blood ratios were between 3.6 and 135.6, correspondingly. (177)Lu-bisphosphonate dimers showed a slightly higher bone accumulation (SUVfemur = 4.48 ± 0.38 for [(177)Lu]Lu-DO2A(P(BP))2; SUVfemur = 5.41 ± 0.46 for [(177)Lu]Lu-DOTA(M(BP))2) but a slower blood clearance (SUVblood = 1.25 ± 0.09 for [(177)Lu]Lu-DO2A(P(BP))2; SUVblood = 1.43 ± 0.32 for [(177)Lu]Lu-DOTA(M(BP))2). CONCLUSIONS: Lu-complexes of macrocyclic bisphosphonates might become options for the therapy of skeletal metastases in the near future, since they show high uptake in bone together with a very low soft-tissue accumulation.

Synthesis and preliminary in vivo evaluation of well-dispersed biomimetic nanocrystalline apatites labeled with positron emission tomographic imaging agents.

In recent years, biomimetic synthetic apatite nanoparticles (AP-NPs), having chemical similarity with the mineral phase of bone, have attracted a great interest in nanomedicine as potential drug carriers. To evaluate the therapeutic perspectives of AP-NPs through the mechanisms of action and organs they interact with, the noninvasive monitoring of their in vivo behavior is of paramount importance. To this aim, here the feasibility to radiolabel AP-NPs ("naked" and surface-modified with citrate to reduce their aggregation) with two positron emission tomographic (PET) imaging agents ([(18)F]NaF and (68)Ga-NO2AP(BP)) was investigated. [(18)F]NaF was used for the direct incorporation of the radioisotope into the crystal lattice, while the labeling by surface functionalization was accomplished by using (68)Ga-NO2AP(BP) (a new radio-metal chelating agent). The labeling results with both tracers were fast, straightforward, and reproducible. AP-NPs demonstrated excellent ability to bind relevant quantities of both radiotracers and good in vitro stability in clinically relevant media after the labeling. In vivo PET studies in healthy Wistar rats established that the radiolabeled AP-NPs gave significant PET signals and they were stable over the investigated time (90 min) since any tracer desorption was detected. These preliminary in vivo studies furthermore showed a clear ability of citrated versus naked AP-NPs to accumulate in different organs. Interestingly, contrary to naked AP-NPs, citrated ones, which unveiled higher colloidal stability in aqueous suspensions, were able to escape the first physiological filter, i.e., the lungs, being then accumulated in the liver and, to a lesser extent, in the spleen. The results of this work, along with the fact that AP-NPs can be also functionalized with targeting ligands, with therapeutic agents, and also with metals for a combination of different imaging modalities, make AP-NPs very encouraging materials for further investigations as theranostic agents in nanomedicine.

Development of a [177Lu]BPAMD labeling kit and an automated synthesis module for routine bone targeted endoradiotherapy.

Painful bone lesions, both benign and metastatic, are often managed using conventional analgesics. However, the treatment response is not immediate and is often associated with side-effects. Radionuclide therapy is used for pain palliation in bone metastases as well as some benign neoplasms. Endoradiotherapy has direct impact on the pain-producing bone elements, and hence, response is significant, with minimal or no side-effects. A new potential compound for endoradiotherapy is [(177)Lu]BPAMD. It combines a highly affine bisphosphonate, covalently bridged with DOTA through an amide bond, with the low-energy ß(-) emitting therapeutic radiolanthanide (177)Lu. For routine chemical application, an automated synthesis of this radiopharmaceutical and a Kit-type labeling procedure appears to be a basic requirement for its good manufacturing practice (GMP) based production. A Kit formulation combining BPAMD, acetate buffer, and ethanol resulted in almost quantitative labeling yields. The use of ethanol and ascorbic acid as quenchers prevented radiolysis over 48 hours. An automated synthesis unit was designed for the production of therapeutic doses of [(177)Lu]BPAMD up to 5 GBq. The procedure was successfully applied for patient treatments.

Gallium(III) complexes of NOTA-bis (phosphonate) conjugates as PET radiotracers for bone imaging.

Ligands with geminal bis(phosphonic acid) appended to 1,4,7-triazacyclonone-1,4-diacetic acid fragment through acetamide (NOTAM(BP) ) or methylenephosphinate (NO2AP(BP) ) spacers designed for (68) Ga were prepared. Ga(III) complexation is much faster for ligand with methylenephosphinate spacer than that with acetamide one, in both chemical (high reactant concentrations) and radiolabeling studies with no-carrier-added (68) Ga. For both ligands, formation of Ga(III) complex was slower than that with NOTA owing to the strong out-of-cage binding of bis(phosphonate) group. Radiolabeling was efficient and fast only above 60 °C and in a narrow acidity region (pH ~3). At higher temperature, hydrolysis of amide bond of the carboxamide-bis(phosphonate) conjugate was observed during complexation reaction leading to Ga-NOTA complex. In vitro sorption studies confirmed effective binding of the (68) Ga complexes to hydroxyapatite being comparable with that found for common bis(phosphonate) drugs such as pamindronate. Selective bone uptake was confirmed in healthy rats by biodistribution studies ex vivo and by positron emission tomography imaging in vivo. Bone uptake was very high, with SUV (standardized uptake value) of 6.19 ± 1.27 for [(68) Ga]NO2AP(BP) ) at 60 min p.i., which is superior to uptake of (68) Ga-DOTA-based bis(phosphonates) and [(18) F]NaF reported earlier (SUV of 4.63 ± 0.38 and SUV of 4.87 ± 0.32 for [(68) Ga]DO3AP(BP) and [(18) F]NaF, respectively, at 60 min p.i.). Coincidently, accumulation in soft tissue is generally low (e.g. for kidneys SUV of 0.26 ± 0.09 for [(68) Ga]NO2AP(BP) at 60 min p.i.), revealing the new (68) Ga complexes as ideal tracers for noninvasive, fast and quantitative imaging of calcified tissue and for metastatic lesions using PET or PET/CT.

In vivo comparison of DOTA based 68Ga-labelled bisphosphonates for bone imaging in non-tumour models.

Bone metastases are a class of cancerous metastases that result from the invasion of a tumor into bone. The solid mass which forms inside the bone is often associated with a constant dull ache and severe spikes in pain, which greatly reduce the quality of life of the patient. Numerous (99m)Tc-labeled bisphosphonate functionalised complexes are well established tracers for bone metastases imaging. The objective of this research was to evaluate the pharmacokinetics and behaviour of three DOTA based bisphosphonate functionalised ligands (BPAMD, BPAPD and BPPED), using both (68)Ga µ-PET in vivo imaging and ex vivo biodistribution studies in healthy Wistar rats. The compounds were labelled with (68)Ga in high yields using an ammonium acetate buffer, and subsequently purified using a cation exchange resin. High bone uptake values were observed for all (68)Ga-labelled bisphosphonates at 60 minutes p.i. The highest uptake was observed for [(68)Ga]BPPED (2.6 ± 0.3% ID/g) which compares favourably with that of [(99m)Tc]MDP (2.7 ± 0.1 ID/g) and [(18)F]fluoride (2.4 ± 0.2% ID/g). The (68)Ga-labelled DOTA-bisphosphonates showed rapid clearance from the blood and renal system, as well as low binding to soft tissue, resulting in a high bone to blood ratio (9.9 at 60 minutes p.i. for [(68)Ga]BPPED, for example). Although further studies are required to assess their performance in tumor models, the results obtained suggest that these ligands could be useful both in imaging ((68)Ga) and therapeutic treatment ((177)Lu) of bone metastases.