Lutetium-177 (177Lu) labeled DOTA-3-Tyr-Octreotate (DOTA-TATE) is a peptide-based receptor-mediated radionuclide therapy that has received FDA authorization for treatment of neuroendocrine tumors expressing somatostatin sstr2 receptors. The present study employs a synthetically modified gold nanoparticle (AuNP) preparation for effecting increased delivery of [177Lu]Lu-DOTA-TATE at the targeted cancerous site. Two synthetic approaches, viz. pre-labeling and post-labeling, were followed to produce the [177Lu]Lu-DOTA-TATE-loaded AuNPs. The pre-labeling approach estimated the peptide functionalization to an extent of similar to 20%. TEM of DOTA-TATE functionalized AuNPs yielded a particle size around 5.5 +/- 2.2 nm. A theoretical estimate quantified the average number of TATE molecules per AuNP around 23. IC50 determination of DOTA-TATE functionalized AuNP using [177Lu]Lu-DOTA-TATE as a standard in AR42J cell lines exhibited superior inhibition (0.62 nM) in comparison to free DOTA-TATE peptide (4.84 nM). The radiolabeled AuNPs presented >80% specificity in AR42J cell lines. Biodistribution studies of radiolabeled AuNPs in AR42J tumor xenografts showed tumor uptake of 1.76 +/- 1.08% ID/g at 2 h post-injection (p.i.), which remained nearly constant over a period of 48 h. Unlike the standard [177Lu]Lu-DOTA-TATE radiotracer, the NP elimination from the blood pool was slower; however, prolonged systemic circulation failed to enhance tumor accumulation over time.

[131I]meta-iodobenzylguanidine (mIBG) in variable dosage forms is widely used for the therapy of neuroendocrine tumors. Our group previously reported a 99mTc analogue of [131I]mIBG that demonstrated high specificity in vitro towards norepinephrine transporter (NET)-positive neuroblastoma cells. Considering that the 99mTc/188Re pair serves as a useful theranostic combination, we herein describe the synthesis of its 188Re analogue and evaluate its potential for therapeutic applications. A benzylguanidine derivative functionalized at the meta position via an isonitrile moiety ("1") was employed for 188Re complexation following Re-"4 + 1" chemistry. Synthesized 188Re complex 6 was evaluated in NET-positive SK-N-SH neuroblastoma cells and corresponding xenograft models. Cellular uptake studies revealed that the 188Re complex 6 exhibited ~50% of the uptake observed for [125I]mIBG. Nonetheless, it retained significant NET specificity (~60%), as confirmed by inhibition experiments using desmethylimipramine (DMI). Biodistribution studies in SK-N-SH xenograft-bearing mice demonstrated tumor uptake of 4.07 ± 0.08%ID/g at 30 min (p > 0.05), with significant retention up to 3 h (4.99 ± 0.08%ID/g). Tumor uptake was shown to be NET-specific, as pre-treatment with excess DMI significantly inhibited tracer accumulation in vivo. Bioevaluation of the synthesized 188Re complex 6 confirmed its affinity for NETs; however, limited in vivo stability restricted its suitability for therapeutic application.

DUPA (2-[3-(1,3-dicarboxy propyl) ureido] pentanedioic acid) is a known small molecule prostate-specific membrane antigen (PSMA) enzyme inhibitor that targets the PSMA receptor found overexpressed on prostate cancer. The present work synthesizes and evaluates a Tc-99m (technetium) "metal essential" glutamate complex, which mimics the DUPA ligand, for its potential use in SPECT imaging of PSMA-positive prostate cancers. Glutamic acid was synthetically modified on treatment with carbon disulfide in the presence of sodium carbonate to yield glutamate-dithiocarbamate (gDTC) in moderate yields (similar to 60%). To a freshly prepared [[Tc-99m]Tc equivalent to N](2+) intermediate, gDTC was added to yield the final complex in high radiochemical yield and purity (>95%). The complex was then bio-evaluated in vitro in PSMA-positive LNCaP cell lines in comparison to the standard [Lu-177]Lu-PSMA-617 tracer. [Tc-99m]Tc-analogue of DUPA ligand showed uptake in LNCaP cells (similar to 9.5%ID/10(6) cells @ 2 h; K-d similar to 25.2 +/- 6.2 nM) in comparison to [Lu-177]Lu-PSMA-617 (similar to 5%ID/10(6) cells @ 2 h), however the percentage specificity observed was only 60% (vs. 90% for [Lu-177]Lu-PSMA-617) as ascertained from inhibition using 2-PMPA (blocker). The in vivo distribution in normal Sprague-Dawley (SD) rats indicated similar pharmacokinetics as that observed for [Lu-177]Lu-PSMA-617. The [Tc-99m]Tc-radiotracer showed high retention in the kidneys as observed for several radiolabeled PSMA analogues.

OBJECTIVE:Primary and secondary hepatic malignancies are a significant cause of cancer-related mortality worldwide. Radioembolization with yttrium-90 (90Y) microspheres has emerged as a promising treatment option for unresectable hepatic tumours. However, the high cost of commercially available Y-90 microspheres, such as 90Y-TheraSphere or 90Y-SirSphere, limits their accessibility in developing countries. We present the first Indian clinical experience of indigenously developed [90Y] Yttria alumino silicate glass microspheres, known as "90Y-BhabhaSphere," for radioembolization of hepatic malignancies. METHODS:"90Y-BhabhaSphere" formulation developed at Bhabha Atomic Research Centre (BARC), Mumbai, was used to treat a small cohort of 5 patients with unresectable hepatic malignancies. The 90Y-BhabhaSphere delivery system was developed through a rigorous process and in vitro tested using a microcatheter connection to simulate the transarterial radioembolization (TARE) procedure. Feasibility, safety, delivery efficiency, and preliminary efficacy of treatment using 90Y-BhabhaSphere were assessed. RESULTS:Our initial clinical experience with 90Y-BhabhaSphere demonstrates its safety and feasibility in treating hepatic malignancies. 90Y-BhabhaSphere demonstrated excellent delivery efficiency, reaching 99% in vitro (dummy run) and 97% in vivo (clinical delivery) 90Y-BhabhaSphere was successfully administered to 4 patients, whereas in 1 patient, the delivery had to be terminated due to a leakage in the delivery system. The treatment was well-tolerated, with minimal adverse effects. Preliminary efficacy analysis shows promising results, with a significant reduction in tumour size and improvement in liver function. CONCLUSION:90Y-BhabhaSphere offers a cost-effective alternative to commercially available 90Y-microspheres. Our initial clinical experience demonstrates its safety, feasibility, and preliminary efficacy in treating hepatic malignancies. Large clinical trials need to be conducted to establish the long-term efficacy and safety of 90Y-BhabhaSphere. ADVANCES IN KNOWLEDGE:This study highlights a key advantage of 90Y-BhabhaSphere: its significantly higher specific activity (approximately 6000 Bq/sphere) compared to commercially available 90Y-TheraSphere (2700 Bq/sphere). This suggests a potential for delivering higher tumour doses while minimizing radiation exposure to healthy liver tissue, thereby reducing the risk of radiation-induced liver damage.

A PLC based semi-automated separation system is described demonstrating the feasibility of no-carrier-added 177 LuCl 3 production for formulation of clinical patient doses.

There is a need for chelators that are versatile for complexing multiple radiometals. We previously demonstrated that the macrocyclic 1,2-HOPO chelator, L804, has utility for complexing 177Lu(III) for radiopharmaceutical therapy and 89Zr(IV) for PET imaging with antibody-based agents. Here, we investigated whether 89Zr-radiolabelled peptidomimetic LLP2A could function as a diagnostic surrogate for [177Lu]Lu-LLP2A therapy in the targeting of VLA-4 overexpressed in melanoma, with and without an albumin-binding moiety (pIBA) for biological half-life extension. METHODS:L804-LLP2A (1) and L804-pIBA-LLP2A (2) were synthesized and radiolabelled with 89Zr and 177Lu. Distribution coefficients, in vitro binding affinity, biodistribution, and PET/SPECT imaging data in the B16F10 tumor-bearing mice model of metastatic melanoma were collected. RESULTS:Quantitative radiochemical yield (>99 %) was achieved with 89Zr and 177Lu within 30 min at 25 °C. Through a shake flask method, the LogD7.4 distribution coefficients of [89Zr]Zr-2 and [177Lu]Lu-2 (-0.67 ± 0.06 and - 1.05 ± 0.10, respectively) indicated greater lipophilicity compared to their non-albumin binder containing analogues, [89Zr]Zr-1 and [177Lu]Lu-1 (-1.67 ± 0.19 and - 1.26 ± 0.12, respectively). The addition of pIBA to the tracer scaffold did not appreciably affect binding affinity of 89Zr- or 177Lu-labeled LLP2A to VLA-4, with the Kd values for [89Zr]Zr-1 vs [89Zr]Zr-2 (2.2 ± 0.2 vs 1.6 ± 0.2 nM) and [177Lu]Lu-1 vs [177Lu]Lu-2 (8.4 ± 1.0 vs 10.8 ± 2.6 nM) being comparable. In B16F10 melanoma tumor-bearing mice, both [89Zr]Zr-1 and [177Lu]Lu-1 exhibited rapid blood clearance but had distinctly different biodistribution profiles. [89Zr]Zr-1 was retained more in the tumor, kidney, and spleen out to 48 h compared to [177Lu]Lu-1. There was a rapid clearance from both tumor and normal tissues for [177Lu]Lu-1 out to 48 h, and aside from the muscle, tumor: non-tumor ratios were overall greater for [177Lu]Lu-1 than those obtained for [89Zr]Zr-1. The albumin-binding [89Zr]Zr-2 and [177Lu]Lu-2 displayed more similar distribution profiles, with higher tumor and non-tumor tissue accumulation, and significantly slower blood clearance. Both tracers gradually cleared out of tumor and non-tumor tissues, although [89Zr]Zr-2 had slightly more retention in the kidney and tumor at 96 h compared to [177Lu]Lu-2. CONCLUSION:The addition of pIBA to LLP2A resulted in a similar distribution profile between [89Zr]Zr-2 and [177Lu]Lu-2 in contrast to the non-pIBA bearing analogues, where the 89Zr and 177Lu agents showed markedly different biodistributions, indicating the benefit of an albumin binding moiety for a matched small-molecule theranostic pair using these chemically disparate isotopes.

Background Prostate cancer affects 1 in 6 men, and it is the second‑leading cause of cancer-related death in American men. Surgery is one of the main treatment modalities for prostate cancer, but it often results in incomplete resection margins or complete resection that leads to nerve damage and undesirable side effects. In the present work, we have developed a new bimodal tracer, NODAGA-sCy7.5 PSMAi (prostate-specific membrane antigen inhibitor), labeled with the true matched theranostic pair 64Cu/67Cu and a near-infrared fluorescent dye. This agent could potentially be used for concomitant PET imaging, optical surgical navigation, and targeted radiopharmaceutical therapy. Methods A prostate-specific membrane antigen (PSMA)-targeting urea derivative was conjugated to NODAGA for copper radiolabeling and to the near-infrared fluorophore sulfo-Cy7.5 (sCy7.5). Binding studies were performed in PSMA-positive PC-3 PIP cells, as well as uptake and internalization assays in PC-3 PIP cells and PSMA-negative PC-3 wild type cells. Biodistribution studies of the 64Cu-labeled compound were performed in PC-3 PIP- and PC-3 tumor-bearing mice, and 67Cu biodistributions of the agent were obtained in PC-3 PIP tumor-carrying mice. PET imaging and fluorescence imaging were also performed, using the same molar doses, in the two mouse models. Results The PSMA conjugate bound with high affinity to PSMA-positive prostate cancer cells, as opposed to cells that were PSMA-negative. Uptake and internalization were rapid and PSMA-mediated in PC-3 PIP cells, while only minimal non-specific uptake was observed in PC-3 cells. Biodistribution studies showed specific uptake in PC-3 PIP tumors, while accumulation in PC-3 tumor-bearing mice was low. Furthermore, tumor uptake of the 67Cu-labeled agent in the PC-3 PIP model was statistically equivalent to that of 64Cu. PET and fluorescence imaging at 0.5 nmol per mouse also demonstrated that PC-3 PIP tumors could be clearly detected, while PC-3 tumors showed no tumor accumulation. Conclusions NODAGA-sCy7.5-PSMAi was specific and selective in detecting PSMA-positive, as opposed to PSMA-negative, tumors in mouse models of prostate cancer. This bioconjugate could potentially be used for PET staging with 64Cu, targeted radiopharmaceutical therapy with 67Cu, and/or image-guided surgery with sCy7.5.

The present work describes the formulation of a lyophilized Fibroblast Activation Protein Inhibitor-4 (FAPI-4) kit for preparation of [68Ga]Ga-FAPI-4 in high radiochemical yield (RCY) using either generator or cyclotron produced 68GaCl3, suitable for Positron Emission Tomography (PET) based diagnosis of cancers over-expressing Fibroblast Activation Protein (FAP). Experimental parameters such as concentration of FAPI-4, buffer content, storage conditions and shelf-life were optimized to ensure > 95

Patient specific treatments for different cancers are currently being actively addressed through nuclear medicine. More recently, the identification of biomarker namely; prostate-specific membrane antigen (PSMA) expressed on the prostate cancer cell surface has been considered as a turning point in prostate cancer management using radiopharmaceuticals. In this treatment method, apart from radionuclide, organic ligands that target PSMA constitute an essential component. PSMA-11 and PSMA-617 are two important ligands that form the radiopharmaceuticals, [Ga-68]Ga-PSMA-11, [Lu-177]Lu-PSMA-617, which are currently powering the prostate cancer management, especially metastatic castration resistant prostate cancer (mCRPC) in most part of the world. Identification of efficient synthetic routes towards these highly expensive ligands is an important prerequisite to make this treatment modality more popular. In this account, the synthetic challenges that we circumvent during the solution phase synthesis of PSMA-11 and PSMA-617, through different chemical synthetic routes are demonstrated. Post-synthesis, both the ligands, PSMA-11 and PSMA-617 were successfully radiolabelled using Ga-68, and Lu-177, respectively, to generate corresponding labelled products [Ga-68]Ga-PSMA-11, and [Lu-177]Lu-PSMA-617, in good radiochemical purity.

Synthesis of PSMA-617, a peptide based ligand used in the preparation of nuclear medicine, Lu-177-PSMA-617, for the treatment of prostate cancer, is demonstrated in 6 steps, starting from appropriately protected amino acid building blocks. A solution phase Boc-strategy was adopted for the synthesis of peptide, wherein deprotection of carbamate group using HCl (g), was employed as the key step. The synthesis furnished PSMA-617 in purity >99.5 % as confirmed by HPLC analysis. ESI-MS and NMR analysis supported the structural integrity of the compound. The synthesized ligand was radiolabelled using Lu-177 to generate the desired radiopharmaceutical, Lu-177-PSMA-617, in radiochemical purity >98 %, as revealed by radio HPLC and TLC analysis. This establishes its potential as a nuclear medicine for therapeutic application.

Folate receptors (FRs) are known to be over-expressed in several human malignancies and therefore serve as an important target for small radiolabeled folate derivatives for non-invasive imaging of tumor, which is an important tool for future treatment recourse. In the present article, we report the synthesis of a new 99mTc-labeled radiotracer for the aforementioned application following the well-established 99mTc-'4+1' chemistry. Formation of the desired [99mTc]Tc-complex with >95% radiochemical purity was confirmed by radio-HPLC and its structure was ascertained by characterizing a natural rhenium analogue of the said complex. Although the ligand exhibited a weaker affinity towards FRs compared to native folic acid (IC50 8.09 µM vs 29.46 nM), the 99mTc-labeled complex was found to bind folate receptor-positive KB cells with high specificity (∼90%). Similar studies in a folate receptor negative cell line viz. A549 further corroborated the receptor-specificity of the synthesized complex. In vivo studies in KB tumor xenograft showed moderate uptake of ∼2.6% upto 3 h post-injection with high specificity (∼80%). The favorable features observed warrant further screening of the current design towards achieving an improved molecular probe for the said application.

The treatment of metastatic Castration Resistant Prostate Cancer (mCRPC) by targeting Prostate Specific Membrane Antigen (PSMA), that is ubiquitously expressed on malicious cells, using177Lu-PSMA-617, has been showing great potential. Considering the promising results from Radioligand Therapy (RLT) studies conducted at multiple centres, 177Lu-PSMA-617, is being considered for FDA approval. The organic ligand, PSMA-617, is therefore in great demand, but it is also an expensive pharmaceutical precursor. We demonstrate here a convenient synthetic protocol for PSMA-617, using a solution phase method. Both, linear and convergent synthetic strategies were explored to affirm that the later approach furnished the target in better yield. The protocol presented here involves the use of commercially and economically viable reagents together with flow reactor based metal catalyzed hydrogenation as vital step. Using the method portrayed, PSMA-617 with purity >99.5% was achieved, while, radiolabelling with 177Lu afforded, 177Lu-PSMA-617 with radiochemical purity >98%, which is adequate for therapeutic applications. 177Lu-PSMA-617 prepared using the synthesized ligand showed parity in purity against that made from commercial equivalent.

The imaging of prostate tumours by targeting Prostate Specific Membrane Antigen (PSMA), using binding tracer, 68Ga-PSMA-11, offer lots of promises for specific detection of prostate associated malignancies. The popularity of 68Ga-PSMA-11 as a radioligand tool for prostate cancer diagnosis has gained a major boost upon its FDA approval in December 2020. Development of an economically benign protocol for the synthesis of PSMA-11, using solution phase method, is particularly important to get a better access to this highly important and expensive Active Pharmaceutical Ingredient (API). The PSMA-11 synthesized using the protocol presented here, involves the use of a flow reactor based catalytic hydrogenation as the key step. Using the method portrayed, PSMA-11 with purity >99.5% was achieved, while, radiolabelling with 68Ga afforded 68Ga-PSMA-11 with radiochemical purity >95%, which is appropriate for imaging applications.

The present work illustrates the feasibility of production and supply of ready-to-use gallium-68 (68Ga) radiopharmaceuticals, similar to [18F]FDG, through a centralized production facility. The supply logistic from centralized facility to various imaging centers situated within the radius of 50 km was investigated using germanium-68/gallium-68 generator system of fixed (1.85 GBq) capacity. However, the logistics discussed and conclusion drawn can be definitely extrapolated to many other 68Ga radiopharmaceuticals, where the 68Ga radioisotope used is produced via direct cyclotron route.

Introduction: Strategic design and synthesis of nanoparticle based preparations could improve diagnostic screening of several cancer types, thereby facilitating better clinical management of the disease. Towards this, the present work aims to develop and evaluate a radioactive technetium-99m (Tc-99m) labeled gold nanoparticle (NP) preparation modified with folic acid, so as to diagnose folate receptor positive cancers viz. ovarian, breast, etc. Methods: 11-Bromoundecanoic acid (UA) was synthetically modified both with folic acid and Hydrazinonicotinic acid (HYNIC) chelate at the carboxylic acid end and subsequently converted to thiol functionality at the bromo terminal to yield folic acid-UA-SH and HYNIC-UA-SH ligands respectively. Gold NPs modified with folic acid and HYNIC chelator were obtained on direct addition of folic acid-UA-SH and HYNIC-UA-SH to chloroauric acid in polysorbate 80 solution under reducing conditions. These NPs were then radiolabeled with Tc-99m following HYNIC labeling approach. Both the inactive and Tc-99m-labeled gold NPs were then tested for their biological efficacy in folate receptor (FR) positive KB cancer cell lines. Also, biodistribution studies of 99mTc-labeled gold NPs were carried in KB tumor xenografts to ascertain the efficacy towards FR in in vivo system. Results: Polysorbate 80 could stabilize the gold NP preparation with average size <10 nm as determined by TEM. Inhibition of [H-3]folic acid with functionalized gold nanoparticle revealed affinity towards FR positive KB cell lines with an IC50 similar to 9 mu M. Biodistribution studies of Tc-99m-labeled gold NP preparation in SCID mice bearing KB tumor showed an uptake of 1.39 +/- 0.18%ID/g in tumor and 5.48 +/- 0.72%ID/g in kidneys at 3 h post-injection. In vivo distribution in folic acid pre-treated animals could not establish the specificity towards folate receptors. Conclusions: Biological evaluation of functionalized gold NP showed affinity towards FR positive cancer cell lines. Tc-99m-labeled NP exhibited target uptake in both in vitro and in vivo models, but folic acid inhibition could not establish the target specificity. Nevertheless, in vivo pharmacokinetics envisaged in the present design was achieved using the present gold functionalized NP preparation. (C) 2020 Elsevier Inc. All rights reserved.

INTRODUCTION:meta-[123/131I]Iodobenzylguanidine (mIBG) is a clinical agent used for imaging neuroendocrine tumors, where uptake in tumor is via active transport mechanism through norepinephrine transporters (NET). Our group in past have evaluated a 99mTc-analogue of the above tracer, based on 99mTc-4 + 1 labeling approach, which exhibited significant affinity for NET but suffered from reduced specific uptake in comparison to reference standard no-carrier-added (n.c.a.) [125I]mIBG. The present work attempts to synthesize two new 99mTc-analogues of the radio-iodinated derivative following [99mTc]Tc(CO)31+ approach with an aim to improve the above specific uptake content.METHODS:Two different precursors, xylylenediamine and 1,3-bis(chloromethyl)benzene, were synthetically modified to yield meta-functionalized benzylguanidine derivatives bearing iminodiacetate (IDA) and aminoethylglycine (AEG) tridentate chelating moieties, respectively. These ligands were labeled with technetium-99m via [99mTc][Tc(CO)3(H2O)3]+ synthon to form desired radioactive complexes 9 and 10. The radiolabeling yields of the complexes obtained were >90% as confirmed by radio-HPLC. The HPLC purified complexes were used for in vitro and in vivo evaluation to understand the true biological efficacy. Structural characterization of the radiolabeled complexes was carried after synthesizing and characterizing their Re-analogues.RESULTS:Cell uptake studies with the radiolabeled complexes in SK-N-SH neuroblastoma cell lines revealed reduced uptake in the cells (<1% of incubated radioactivity/106 cells) in comparison to n.c.a. [125I]mIBG (~12%). However, limited specificity (~60%) was observed for the complexes as ascertained through desmethylimipramine (DMI) inhibition. Biodistribution studies in normal Wistar rats exhibited desired non-target clearance pharmacokinetics for the complexes but in vivo NET efficacy in myocardium for the neutral complex 10 could not be established.CONCLUSIONS:Tridentate [99mTc]Tc(CO)31+ chelation approach severely affects biological behavior of the present small bioactive molecule under study to a significant extent in comparison to monodentate ligation in 99mTc-4 + 1 strategy.

Low dose Methotrexate (MTX) therapy is considered a gold standard for Rheumatoid Arthritis (RA). Transdermal drug delivery is hypothesized as an alternative to conventional therapies to alleviate its adverse effects. In our study, MTX was entrapped in deformable liposomes and loaded in a hydroxyethyl cellulose gel. This system was evaluated by the Box Behnken statistical design for optimization. The effect of formulation variables on particle size, entrapment and ex vivo skin permeation was studied. The MTX nanogel was evaluated for its dermal toxicity (acute and repeat dose safety), in vivo biodistribution (using 125I radio-labelled MTX) and therapeutic efficacy (collagen induced arthritis [CIA] model). The optimized formulation demonstrated appreciable nanosize (110 ± 20 nm), drug entrapment (42 ± 1.9%) and high ex vivo transdermal flux (17.37 ± 1.5 μg/cm2/hr). In the dermal toxicity studies, nanogel formulation did not show any signs of irritation or toxicity, whereas in the biodistribution study, the MTX nanogel formulation depicted sustained systemic delivery up to 48 h with low accumulation in its organs of toxicity such as the liver, kidneys and gut. In the CIA model, the MTX nanogel significantly ameliorated hind paw swelling, reduced arthritic score, joint damage (histological, radiological examination) and attenuated the rise in serum cytokines such as TNF-ɑ and IL-6. In conclusion, the optimized MTX nanogel formulation displayed skin biocompatibility, sustained systemic delivery, safety as well as therapeutic efficacy.

Porphyrins are tetrapyrrolic macrocyclic ligands known for their affinity towards neoplastic tissues and once radiolabeled with a suitable diagnostic radioisotope could potentially be used for the imaging of tumorous lesions. In the present study, an unsymmetrically substituted porphyrin derivative namely 5-(p-amino-propyloxyphenyl)-10,15,20-tris(carboxymethyleneoxyphenyl)-porphyrin was synthesized and modified further to enable radiolabeling with 99mTc using two different 99mTc-cores viz. 99mTc-HYNIC (hydrazino nicotinic acid) and 99mTc(N)PNP2 (PNP2 = bis-[(2-dimethylphosphino)ethyl]-methoxy-ethylamine) in order to study the effect of employing different 99mTc-cores on tumor affinity and pharmacokinetic behavior of the resultant 99mTc-labeled porphyrin complexes. 99mTc-Porphyrin complexes were characterized by reversed phase HPLC studies and could be prepared with >95% radiochemical purity under optimized radiolabeling conditions. Both 99mTc-complexes were found to be adequately stable in human blood serum till 3 h post-preparation. Bio-distribution studies, carried out in Swiss mice bearing fibrosarcoma tumors, revealed relatively higher tumor uptake for the 99mTc-HYNIC-porphyrin complex (3.95 ± 1.42 and 3.28 ± 0.27% IA per g) compared to that exhibited by the 99mTc(N)PNP-DTC-porphyrin complex (1.52 ± 0.53 and 1.56 ± 0.10% IA per g) at 1.5 and 3 h post-administration, although the former complex exhibited comparatively lower lipophilicity in the octanol-water system. Higher uptake and longer retention in the blood were observed for the 99mTc-HYNIC-porphyrin complex (6.63 ± 0.75 and 4.36 ± 0.25% IA per g) compared to that exhibited by the 99mTc(N)PNP-DTC-porphyrin complex (2.41 ± 0.54 and 2.30 ± 0.16% IA per g) at both 1.5 and 3 h post-administration. However, relatively lower liver uptake was observed for the former complex (19.26 ± 3.48 and 18.45 ± 1.05% IA per g) than that exhibited by the latter one (39.37 ± 3.88 and 34.15 ± 8.25% IA per g) at both 1.5 and 3 h post-administration. This study indicates that the in vivo behavior exhibited by the 99mTc-labeled porphyrins not only depends on their lipophilicity/hydrophilicity but is also governed by the Tc-cores employed for radiolabeling.

Introduction: meta-[I-123/131]Iodobenzylguanidine (mIBG) is a clinical agent used for imaging neuroendocrine tumors, where uptake in tumor is via active transport mechanism through norepinephrine transporters (NET). Our group in past have evaluated a Tc-99m-analogue of the above tracer, based on Tc-99m-4 + 1 labeling approach, which exhibited significant affinity for NET but suffered from reduced specific uptake in comparison to reference standard no-carrier-added (n.c.a.) [I-126]mIBG. The present work attempts to synthesize two new Tc-99m analogues of the radio-iodinated derivative following [Tc-99m]Tc(CO)(3)(1+) approach with an aim to improve the above specific uptake content. Methods: Two different precursors, xylylenediamine and 1,3-bis(chloromethyl)benzene, were synthetically modified to yield meta-functionalized benzylguanidine derivatives bearing iminodiacetate (IDA) and aminoethylglycine (AEG) tridentate chelating moieties, respectively. These ligands were labeled with technetium-99m via [Tc-99m][Tc (CO)(3) (H2O)(3)] (+) synthon to form desired radioactive complexes 9 and 10. The radiolabeling yields of the complexes obtained were >90% as confirmed by radio-HPLC. The HPLC purified complexes were used for in vitro and in vivo evaluation to understand the true biological efficacy. Structural characterization of the radiolabeled complexes was carried after synthesizing and characterizing their Re-analogues. Results: Cell uptake studies with the radiolabeled complexes in SK-N-SH neuroblastoma cell lines revealed reduced uptake in the cells (<1% of incubated radioactivity/10(6) cells) in comparison to n.c.a. [I-125]mIBG (similar to 12%). However, limited specificity (similar to 60%) was observed for the complexes as ascertained through desmethylimipramine (DMI) inhibition. Biodistribution studies in normal Wistar rats exhibited desired non-target clearance pharmacokinetics for the complexes but in vivo NET efficacy in myocardium for the neutral complex 10 could not be established. Conclusions: Tridentate [Tc-99m]Tc(CO)(3)(1+) chelation approach severely affects biological behavior of the present small bioactive molecule under study to a significant extent in comparison to monodentate ligation in Tc-99m-4 + 1 strategy. (C) 2019 Elsevier Inc. All rights reserved.