Technetium-99m monoclonal antibody fragment (FAb) scintigraphy in the evaluation of small cell lung cancer: a preliminary report

Small cell lung cancer (SCC) has the most rapid growth rate of the four cell types and metastasizes early. Present imaging modalities for staging include chest x-ray, CT, MRI and bone scans. In this preliminary study, we assessed the clinical role of ^99mTc-monoclonal antibody (MOAB) scintigraphy in five patients with histologically proven SCC. Each patient was infused with 20–30 mCi of ^99mTc labeled Fab fragment of MOAB (NR-LU-10, NeoRx, Seattle, Wash.). Total body simultaneous anterior and posterior images were obtained 14–16 h post injection. SPECT images of the chest were obtained through a 360 ° rotation of the gamma camera and recorded on a 62 × 64 × 16 matrix. Images (1.2cm thick) were generated in transaxial, sagittal and coronal views.Fourteen of fifteen chest lesions detected by CT were confirmed by ^99mTc MOAB scintigraphy. Scintigraphy detected one additional chest lesion not seen by CT. Scintigraphy failed to detect a brain lesion (2 cm), a chest lesion, and two adrenal lesions, all of which were seen by CT. In one patient with multiple (more than 10) lesions in the liver, both scintigraphy and CT detected all lesions. Three spine lesions seen on ^99mTc MDP scan and positive for metastasis on MRI concentrated ^99mTc MOAB, but two rib lesions seen on ^99mTc MDP bone scan did not concentrate ^99mTc MOAB. It is concluded from these preliminary results that the potential usefulness of ^99mTc MOAB scintigraphy as a complementary imaging modality in the staging of small cell lung cancer should be investigated further.     

Skeletal Scintigraphy: The Use of Technetium 99M-Labeled Complexes in the Detection of Early Osseous Involvement by Metastatic Tumors

Skeletal scintigraphy using Technetium-99m (^99mTc) complexes was carried out in a series of 332 cancer patients. The results of scintigraphy were compared with the results of roentgenography and with the diagnostic usefulness of serum alkaline and acid phosphatase levels and the presence or absence of bone pain. In 25 percent of cases, lesions were first identified with scintigraphs. When metastastic lesions were present on both scintigraphs and roentgenograms, the number was greater on scintigraphs in 72 percent of cases. Six false negative studies were recorded (1 percent). Sixty percent of patients with early metastasis—that is, those with abnormal scintigraphs and negative roentgenograms—were asymptomatic. Serum alkaline and acid phosphatase levels were normal in 40 percent and 42 percent respectively of those with early skeletal involvement. Skeletal scintigraphy with ^99mTc complexes is superior to other commonly employed techniques used to assess bone metastasis.     

Apport de la scintigraphie au 99mTc-dépréotide pour le diagnostic de lésions osseuses secondaires dans le cancer bronchopulmonaire non à petites cellules stade III–IV

ObjectiveIn non-small cell lung cancer (NSCLC), metastatic bone involvement is usually assessed using conventional ^99mTc-HMDP bone scintigraphy, which has a high sensitivity but a poor specificity. The purpose of this study was to assess the usefulness of the ^99mTc-D scintigraphy for the detection of malignant bone metastases in patients with NSCLC stage III or IV and to compare these results with ^99mTc-HMDP bone scan findings.MethodsNineteen patients (13 M and 6 F, mean age 59 years) with proven NSCLC, suspected to have stage III or IV were enrolled prospectively. All patients underwent whole body ^99mTc-HMDP and ^99mTc-D scintigraphy to detect bone metastases within a mean interval of 14 days. Each focal uptake of ^99mTc-D or ^99mTc-HMDP was considered benign or malignant, leading to positive or negative diagnosis for bone involvement. The final diagnosis of bone metastases was established by a lung specialist, on the basis of additional imaging modalities and of 12 months follow-up.ResultsTwelve bone lesions were identified by ^99mTc-D scintigraphy, 10 were classified as bone metastases and two were classified as inflammatory bone lesions. Four patients were metastatic. Fifty eight bone lesions were detected by ^99mTc-HMDP scintigraphy, 26 of whom were considered malignant, eight patients were thus considered metastatic. Thereby, the two nuclear medicine modalities were concordant for 13 patients, that is 68% of cases and were discordant for six patients, representing 32% of cases. Diagnostic sensitivity, specificity and accuracy of depreotide scintigraphy and ^99mTc-HMDP bone scintigraphy were 75% for both, 93.3 and 73.3%, and 89.5 and 73.3% respectively.ConclusionOur data suggest that depreotide scintigraphy with the same sensitivity, a better accuracy and specificity than those of ^99mTc-HMDP bone scan can detect metastatic bone lesions in patients with NSCLC suspected to have stage III or IV disease.     

Comparison of 99mTc-3PRGD2 Integrin Receptor Imaging with 99mTc-MDP Bone Scan in Diagnosis of Bone Metastasis in Patients with Lung Cancer: A Multicenter Study

Purpose

^99mTc-3PRGD2, a promising tracer targeting integrin receptor, may serve as a novel tumor-specific agent for single photon emission computed tomography (SPECT). A multi-center study was prospectively designed to evaluate the diagnostic accuracy of ^99mTc-3PRGD2 imaging for bone metastasis in patients with lung cancer in comparison with the conventional ^99mTc-MDP bone scan.

Methods

The patients underwent whole-body scan and chest tomography successively at both 1 h and 4 h after intravenous injection of 11.1 MBq/Kg ^99mTc-3PRGD2. ^99mTc-MDP whole-body bone scan was routinely performed within 1 week for comparison. Three experienced nuclear medicine physicians blindly read the ^99mTc-3PRGD2 and ^99mTc-MDP images. The final diagnosis was established based on the comprehensive assessment of all available data.

Results

A total of 44 patients (29 male, 59±10 years old) with suspected lung cancer were recruited from 4 centers. Eighty-nine bone lesions in 18 patients were diagnosed as metastases and 23 bone lesions in 9 patients were benign. In a lesion-based analysis, ^99mTc-3PRGD2 imaging demonstrated a sensitivity, specificity, and accuracy of 92.1%, 91.3%, and 92.0%, respectively. The corresponding diagnostic values for ^99mTc-MDP bone scan were 87.6%, 60.9%, and 82.1%, respectively in the same patients. ^99mTc-MDP bone scan had better contrast in most lesions, whereas the ^99mTc-3PRGD2 imaging seemed to be more effective to exclude pseudo-positive lesions and detect bone metastases without osteogenesis.

Conclusion

^99mTc-3PRGD2 is a novel tumor-specific agent based on SPECT technology with a promising value in diagnosis of bone metastasis in patients with lung cancer.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01737112","term_id":"NCT01737112"}}NCT01737112     

Preparation and biological behaviour of some neutral 99mTc-carbonyl dithiocarbamates showing rapid hepatobiliary excretion

A simple procedure for the preparation of ^99mTc—carbonyl complexes of dithiocarbamates in high yield and radiochemical purity has been developed and used for the preparation of ^99mTc—carbonyl complexes of bis(2-hydroxyethyl)dithiocarbamate and bis(2-hydroxypropyl)dithiocarbamate. These complexes were found to be extremely stable and their biological behaviour was studied in mice and compared to that of the ^99mTcN- and the ^99mTc-complexes [prepared by dithionite (dit) reduction] of the same ligands. The carbonyl complexes were found to be efficient hepatobiliary agents and cleared more rapidly than the corresponding ^99mTcN- and ^99mTc(dit)-complexes.     

99mTc/Re complexes based on flavone and aurone as SPECT probes for imaging cerebral β-amyloid plaques

Two ^99mTc/Re complexes based on flavone and aurone were tested as potential probes for imaging β-amyloid plaques using single photon emission computed tomography. Both ^99mTc-labeled derivatives showed higher affinity for Aβ(1–42) aggregates than did ^99mTc-BAT. In sections of brain tissue from an animal model of AD, the Re-flavone derivative 9 and Re-aurone derivative 19 intensely stained β-amyloid plaques. In biodistribution experiments using normal mice, ^99mTc-labeled flavone and aurone displayed similar radioactivity pharmacokinetics. With additional modifications to improve their brain uptake, ^99mTc complexes based on the flavone or aurone scaffold may serve as probes for imaging cerebral β-amyloid plaques.     

Role of serum albumin as a carrier of 99mTc-complex to tumor tissue

To elucidate a factor required for tumor-imaging ^99mTc-labeled radiopharmaceuticals, in vivo behaviors of ^99mTc-l-cysteine (^99mTc-Cys) and ^99mTc-2-mercaptoethylamine (^99mTc-ME) were compared with that of ^99mTc-dl-homocysteine (^99mTc-Hcy) which had been found to accumulate in several experimental tumors. When these three complexes were intravenously injected into mice bearing Ehrlich solid tumor, their tumor affinity was found to depend on their binding ability to serum albumin; ^99mTc-Hcy, the albumin-binding ability of which was highest of the three, was the most tumor-tropic. When the albumin-bound complexes of these three were injected, their tumor distributions were enlarged. These results suggest the importance of serum albumin in serving as a carrier for the transport of ^99mTc-Hcy-related compounds to tumor tissue.     

Analysis of elimination mechanisms of some 99mTc-complexes

The biological behaviour of complexes of ^99mTc with aminopolycarboxylic and aminocarbohydroxamic ligands EDTA (ethylenediaminetetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), EDTAH (ethylenediaminetetraacetohydroxamic acid) and HIDAmH (N-2-hydroxyethyl-N-carboxymethyl-aminoacetohydroxamic acid) was studied in rabbits. The pharmacokinetic parameters determined in intact rabbits were compared with the results obtained in the study of renal and hepatic clearance of the complexes under study. Hepatobiliary excretion, which in [^99mTc]EDTA forms 20–30% of the total excreted amount, is of negligible magnitude in the other ^99mTc-complexes studied (<2%). Their renal clearance is not influenced by the inhibition of tubular secretion with probenecid. Binding to plasma proteins increases in the order [^99mTc]DTPA < [^99mTc]EDTA <[^99mTc]HIDAmH <[^99mTc]EDTAH and the elimination half-life increases in the same order. The value of renal clearance of the complexes studied related to inulin clearance correlates well with the fraction of the free drug in the plasma. In rabbits the complexes under study are excreted mainly by the mechanism of glomerular filtration in the kidney.     

Capillary electrophoresis of technetium radiopharmaceuticals

Diagnostically used ^99mTc kit radiopharmaceuticals were analyzed using capillary zone electrophoresis with radioactivity detection: ^99mTc-bis(bis(2-ethyloxyethyl)phosphino)ethane (^99mTc-Myoview, ^99mTc-Tetrofosmin), ^99mTc-trans(1,2-bis(dehydro-2,2,5,5,-tetramethyl-3-furanone-4-methylene-amino)ethane)-tris(3-methoxy-1-propyl)phosphine) (^99mTc-Technescan Q12, ^99mTc-Furifosmin), ^99mTc-methoxyisobutylisonitrile (^99mTc-MIBI), ^99mTc- , -ethylenecysteine diethylester dimer (^99mTc-ECD), ^99mTc-d,l-hexamethylene propyleneamine oxime (^99mTc-HMPAO), ^99mTc-diethylenetriaminepentaacetic acid (^99mTc-DTPA), ^99mTc-ethylene hepatobiliary iminodiacetic acid (^99mTc-EHIDA), ^99mTc- , -ethylenecysteine dimer (^99mTc-EC), ^99mTc-mercaptoacetylglycylglycylglycine (^99mTc-MAG₃), ^99mTc-dimercaptosuccinic acid (^99mTc-DMSA), ^99mTc-methylene diphosphonate (^99mTc-MDP) and ^99mNaTcO₄. A pressure-driven capillary zone electrophoresis was employed to detect small anions of high electrophoretic mobility and cations within one run. Effective ^99mTc complex charges could be determined by a neutral internal standard. All complexes showed the expected electrophoretic behaviours in view of their charges. Pure products were obtained for the majority of the studied complexes. In the case of ^99mTc-Q12, ^99mTc-EHIDA and ^99mTc-MDP, complex mixtures were detected. The high potential of CE for the analysis of ^99mTc radiopharmaceuticals could be shown.     

Capillary electrophoresis of 99mtechnetium radiopharmaceuticals

Diagnostically used ^99mTc kit radiopharmaceuticals were analyzed using capillary zone electrophoresis with radioactivity detection: ^99mTc-bis(bis(2-ethyloxyethyl)phosphino)ethane (^99mTc-Myoview, ^99mTc-Tetrofosmin), ^99mTc-trans(1,2-bis(dehydro-2,2,5,5,-tetramethyl-3-furanone-4-methylene-amino)ethane)-tris(3-methoxy-1-propyl)phosphine) (^99mTc-Technescan Q12, ^99mTc-Furifosmin), ^99mTc-methoxyisobutylisonitrile (^99mTc-MIBI), ^99mTc-l,l-ethylenecysteine diethylester dimer (^99mTc-ECD), ^99mTc-d,l-hexamethylene propyleneamine oxime (^99mTc-HMPAO), ^99mTc-diethylenetriaminepentaacetic acid (^99mTc-DTPA), ^99mTc-ethylene hepatobiliary iminodiacetic acid (^99mTc-EHIDA), ^99mTc-l,l-ethylenecysteine dimer (^99mTc-EC), ^99mTc-mercaptoacetylglycylglycylglycine (^99mTc-MAG₃), ^99mTc-dimercaptosuccinic acid (^99mTc-DMSA), ^99mTc-methylene diphosphonate (^99mTc-MDP) and ^99mNaTcO₄. A pressure-driven capillary zone electrophoresis was employed to detect small anions of high electrophoretic mobility and cations within one run. Effective ^99mTc complex charges could be determined by a neutral internal standard. All complexes showed the expected electrophoretic behaviours in view of their charges. Pure products were obtained for the majority of the studied complexes. In the case of ^99mTc-Q12, ^99mTc-EHIDA and ^99mTc-MDP, complex mixtures were detected. The high potential of CE for the analysis of ^99mTc radiopharmaceuticals could be shown.     

Preparation,HPLC studies and biological behaviour of 99mTc- and 99mTcN-radiopharmaceuticals based on quinoline type ligands

^99mTc-Complexes of oxine (ox), thiooxine (tox) and 8-hydroxy-5-quinolinesulphonic acid (HQS) were prepared by ligand exchange of ^99mTcNCl₄⁻ and by stannous and dithionite reduction of ^99mTcO₄⁻. HPLC studies showed that the ^99mTcN-tox preparation was almost pure TcN(tox)₂. ^99mTc(Sn)-ox yielded a number of peaks upon HPLC with the major peak being identified as TcO(ox)₂Cl. No other Tc-complexes responsible for other chromatographic peaks were identified. Biodistribution studies in mice showed that all complexes except ^99mTc-HQS were cleared essentially by the hepatobiliary pathway. The ^99mTc-HQS preparations showed increased renal clearance due to the increased aqueous solubility of the complexes resulting from the presence of the sulphonate group on the quinoline ring.     

Development of 99mTc-labeled asymmetric urea derivatives that target prostate-specific membrane antigen for single-photon emission computed tomography imaging

Prostate-specific membrane antigen (PSMA) is expressed strongly in prostate cancers and is, therefore, an attractive diagnostic and radioimmunotherapeutic target. In contrast to previous reports of PMSA-targeting ^99mTc-tricarbonyl complexes that are cationic or lack a charge, no anionic ^99mTc-tricarbonyl complexes have been reported. Notably, the hydrophilicity conferred by both cationic and anionic charges leads to rapid hepatobiliary clearance, whereas an anionic charge might better enhance renal clearance relative to a cationic charge. Therefore, an improvement in rapid clearance would be expected with either cationic or anionic charges, particularly anionic charges. In this study, we designed and synthesized a novel anionic ^99mTc-tricarbonyl complex ([^99mTc]TMCE) and evaluated its use as a single-photon emission computed tomography (SPECT) imaging probe for PSMA detection. Direct synthesis of [^99mTc]TMCE from dimethyl iminodiacetate, which contains both the asymmetric urea and succinimidyl moiety important for PSMA binding, was performed using our microwave-assisted one-pot procedure. The chelate formation was successfully achieved even though the precursor included a complicated bioactive moiety. The radiochemical yield of [^99mTc]TMCE was 12–17%, with a radiochemical purity greater than 98% after HPLC purification. [^99mTc]TMCE showed high affinity in vitro, with high accumulation in LNCaP tumors and low hepatic retention in biodistribution and SPECT/CT studies. These findings warrant further evaluation of [^99mTc]TMCE as an imaging agent and support the benefit of this strategy for the design of other PSMA imaging probes.     

Evaluation of a DMSA kit for instant preparation of 99mTc(V)—DMSA for tumour and metastasis scintigraphy

A kit has been developed to instantly prepare ^99mTc(V)—DMSA. The freeze-dried kit consisting of DMSA, stannous chloride and ascorbic acid in appropriate proportions, produces quality ^99mTc(V)—DMSA when mixed with 0.2 mL of 3.5% NaHCO₃ solution and 2–4 mL of [^99mTc] pertechnetate. The radiopharmaceutical characterized by chromatography with ITLC-SG in 0.9% saline and horizontal paper electrophoresis in 50 mM vernol buffer, pH 8.6, at a potential gradient of 15 V/cm showed a different mobility with respect to ^99mTc(III)-DMSA, a known agent for kidney imaging. The new agent exhibited less plasma protein binding as compared to that of ^99mTc(III)-DMSA. Biodistribution of the pentavalent DMSA in mouse demonstrated greater uptake in bone and muscle and lower uptake in liver and kidney with respect to trivalent DMSA. The soft tissue tumour specificity and its suitability for tumour scintigraphy was apparent from the scintigrams of mammary carcinoma in a C₃H Jax mouse and medullary carcinoma in a patient. Brain metastatic lesions were also visible in a breast carcinoma patient after administering him with the agent.     

Diagnostic d’une fracture occulte isolée de la marge postérieure du tibia par la TEMP–TDM

We report the case of a 56-year-old woman, investigated for pains of the right ankle related to a traumatism of an unspecified mechanism. The radiographic assessment was negative. The ^99mTc-HDP 3-phase bone scintigraphy highlighted, on the blood pool and the delayed images, a located lesion on the right ankle. The single photon emission computerized tomography guided by computerized tomography (SPECT-CT) showed a focused uptake on the posterior margin of the right tibia and a sharp lucent line within the tomoscintigraphic spot of uptake. The diagnosis accepted was an isolated occult fracture of the posterior margin of the right tibia. The contribution of the ^99mTc-HDP 3-phase bone scintigraphy combined with the SPECT-CT in the diagnosis of the occult fractures is discussed.     

99mTc-3P4-RGD2 Scintimammography in the Assessment of Breast Lesions: Comparative Study with 99mTc-MIBI

Purpose

To compare the potential application of ^99mTc-3P-Arg-Gly-Asp (^99mTc-3P₄-RGD₂) scintimammography (SMM) and ^99mTc-methoxyisobutylisonitrile (^99mTc-MIBI) SMM for the differentiation of malignant from benign breast lesions.

Method

Thirty-six patients with breast masses on physical examination and/or suspicious mammography results that required fine needle aspiration cytology biopsy (FNAB) were included in the study. ^99mTc-3P₄-RGD₂ and ^99mTc-MIBI SMM were performed with single photon emission computed tomography (SPECT) at 60 min and 20 min respectively after intravenous injection of 738±86 MBq radiotracers on a separate day. Images were evaluated by the tumor to non-tumor localization ratios (T/NT). Receiver operating characteristic (ROC) curve analysis was performed on each radiotracer to calculate the cut-off values of quantitative indices and to compare the diagnostic performance for the ability to differentiate malignant from benign diseases.

Results

The mean T/NT ratio of ^99mTc-3P₄-RGD₂ in malignant lesions was significantly higher than that in benign lesions (3.54±1.51 vs. 1.83±0.98, p<0.001). The sensitivity, specificity, and accuracy of ^99mTc-3P₄-RGD₂ SMM were 89.3%, 90.9% and 89.7%, respectively, with a T/NT cut-off value of 2.40. The mean T/NT ratio of ^99mTc-MIBI in malignant lesions was also significantly higher than that in benign lesions (2.86±0.99 vs. 1.51±0.61, p<0.001). The sensitivity, specificity and accuracy of ^99mTc-MIBI SMM were 87.5%, 72.7% and 82.1%, respectively, with a T/NT cut-off value of 1.45. According to the ROC analysis, the area under the curve for ^99mTc-3P₄-RGD₂ SMM (area = 0.851) was higher than that for ^99mTc-MIBI SMM (area = 0.781), but the statistical difference was not significant.

Conclusion

^99mTc-3P₄-RGD₂ SMM does not provide any significant advantage over the established ^99mTc-MIBI SMM for the detection of primary breast cancer. The T/NT ratio of ^99mTc-3P₄-RGD₂ SMM was significantly higher than that of ^99mTc-MIBI SMM. Both tracers could offer an alternative method for elucidating non-diagnostic mammograms.     

Radioisotopic Bone Scintigraphy with the Gamma Camera in the Investigation of Prostatic Cancer

Experience with x-rays, strontium-87m scintigraphy, and technetium-99m polyphosphate scintigraphy in the identification of bone metastases in 201 patients with prostatic cancer is reviewed. About 40% of the patients had demonstrable metastases in bone at the time of first presentation.Comparative studies of 247 x-ray and ^87mSr surveys indicated that x-rays failed to detect metastases in 10% of cases where they were identified by ^87mSr but that the isotopic survey similarly failed to detect radiologically evident deposits in 7% of cases.Similar studies comparing ^99mTc polyphosphate surveys with x-ray scans showed that x-rays missed isotopically detected metastases in 12% of cases, but in only one survey out of 67 did the isotope miss radiologically evident deposits. In a series of 32 patients investigated by both isotopic techniques ^99mTc polyphosphate did not fail to detect any metastases and identified deposits in one patient in whom they were missed by ^87mSr scintigraphy. About 15% of both x-ray and ^87mSr surveys gave equivocal results, but only 3% (2 out of 67) of ^99mTc polyphosphate surveys were equivocal.We concluded that ^99mTc polyphosphate bone scintigraphy with the gamma camera was the most reliable of the techniques used for the identification of bone metastases in patients with carcinoma of the prostate. The results of scintigraphy with ^87mSr suggested that serial surveys may provide early evidence of hormone resistance in prostatic cancer.     

Evaluation of 99mTc-mercaptoacetyltripeptides in mice and a baboon

Different derivatives of MAG₃ carrying amino acids such as d- or l-alanine, d-serine, d-2-aminobutyric acid, d-valine or d-phenylglycine were synthesized and their ^99mTc-complexes were evaluated in mice and a baboon. The efficiency of renal handling of the examined ^99mTc-complexes is influenced not only by their lipophilicity but also to a great extent by their configuration and the site of substitution. The renal excretion characteristics of ^99mTc-MAGAG-DA are superior to those of ^99mTc-MAG₃ and the studied ^99mTc-complexes in both animal species.In an attempt to improve the renal handling of ^99mTc-MAG₃ and to evaluate the effect of derivatization we have synthesized different derivatives of MAG₃ in which one or more glycyl groups are replaced by other amino acids such as d- or l-alanine, D-serine, D-2-aminobutyric acid, D-valine or D-phenylglycine. Due to the presence of a chiral centre in the ligand core, exchange labelling of each of the MAG₃ derivatives results in the formation of two diastereomeric technetium complexes. These isomers were separated by HPLC and evaluated in mice. Biodistribution in mice indicates that the efficiency of renal handling of the examined ^99mTc-complexes is not only influenced by their lipophilicity but also to a great extent by their configuration. The renal excretion characteristics of isomer dA of ^99mTc-MAGAG in mice are superior to those of all other studied ^99mTc-complexes and also of the reference compound [¹³¹I]Hippuran. The isomers lB of several alanyl derivatives of ^99mTc-MAG₃ exhibit a pronounced renal retention in both mice and baboon. The results of the evaluation in a baboon confirm the superiority of ^99mTc-MAGAG-dA over ^99mTc-MAG₃ and the other studied ^99mTc-complexes.     

Biolocalization and cell labeling properties of neutral-lipophilic 99mTc-amine-phenol chelates

^99mTc-diamine-diphenol chelates are neutral lipophilic chelates exhibiting good stability in aqueous solutions. The cell labeling and biolocalization properties of four different ^99mTc-amine-phenol complexes were determined. All four chelates readily labeled leukocytes and RCBs in high yields. Even though ^99mTc was retained by the cells, the elution rate of ^99mTc from the labeled cells in plasma at 37 °C was unacceptably high for potential utility in scintigraphic imaging. The uptake of ^99mTc in brain or heart following i.v. injection of the chelates in rats was low and clearance of activity from the blood was slow.     

A new bisphosphonate-containing <Superscript>99m</Superscript>Tc(I) tricarbonyl complex potentially useful as bone-seeking agent: synthesis and biological evaluation

Aiming to develop new bone-seeking radiotracers based on the organometallic core fac-[^99mTc(CO)₃]⁺ with improved radiochemical and biological properties, we have prepared new conjugates with phosphonate pendant groups. The conjugates comprise a chelating unit for metal coordination, which corresponds to a pyrazolyl-containing backbone (pz) with a N,N,N donor-atom set, and a pendant diethyl phosphonate (pz-MPOEt), phosphonic acid (pz-MPOH) or a bisphosphonic acid (pz-BPOH) group for bone targeting. Reactions of the conjugates with the precursor [^99mTc(H₂O)₃(CO)₃]⁺ yielded (mote than 95%) the single and well-defined radioactive species [^99mTc(CO)₃(κ³-pz-MPOEt)]⁺ (1a), [^99mTc(CO)₃(κ³-pz-MPOH]⁺ (2a) and [^99mTc(CO)₃(κ³-pz-BPOH)]⁺ (3a), which were characterized by reversed-phase high-performance liquid chromatography . The corresponding Re surrogates (1–3), characterized by the usual analytical techniques, including X-ray diffraction analysis in the case of 1, allowed for macroscopic identification of the radioactive conjugates. These radioactive complexes revealed high stability both in vitro (phosphate-buffered saline solution and human plasma) and in vivo, without any measurable decomposition. Biodistribution studies of the complexes in mice indicated a fast rate of blood clearance and high rate of total radioactivity excretion, occurring primarily through the renal–urinary pathway in the case of complex 3a. Despite presenting moderate bone uptake (3.04 ± 0.47% injected dose per gram of organ, 4 h after injection), the high stability presented by 3a and its adequate in vivo pharmacokinetics encourages the search for new ligands with the same chelating unit and different bisphosphonic acid pendant arms.