**7. Therapeutic applications**

Emerging MoAbs associated with radionuclide(s) to target selective Tumors (antigens) may considered as an early research took place using iodine radionuclides in cancer. Moreover, some of these drugs/compounds are targeting the outer surface of cells, others may interact with the inner surface of the targeted cells. There are many examples for applications of different radiopharmaceutical in diverse therapeutic applications, e.g. nucleosides and their analogues in modulation of both cell proliferation as well as mRNA transcription. Besides imaging of cell proliferation and mRNA transcription, a good advancement had been made to articulate a sort of tracers for imaging cell hypoxia. Interestingly, the progress in radiolabeled agents may exhibit remarkable benefits for speculating the resulted outcomes of tumors to radiotherapy beam which is greatly affected by the potential oxygen of the cell as in cardiac hypoxia. Discovery and search for new radiolpharmaceutical with new therapeutic applications revealed by chance non-nitroimidazole technetium-labeled molecule during a research program at Amersham International which is also trapped by reduction in hypoxic cells and this new agent is currently in the final stage of drug approval.. Several therapy applications are summarized in the next section [7].

#### **7.1 Inflammation and infection**

This area has provided a rich field for radiopharmaceutical research in last few years. Many of the newly developed radiopharmaceuticals products are derived from peptides, antibodies, cytokines, and polypeptides and very much similar to the ones which have been used in cancer [7].

The capability to image the indirect or direct inflammatory response to the infection is the key for clinical management with high selectivity, e.g. Antibiotic complex of Technetium (Ciprofloxacin = Tcinfecton "Tc") [8]. Tc is good for labeling leucocytes to hammer Tc-leucocytes to place of infection. Several other examples, Tc-HMPAO, Tc-ECD, Tc-citrate, and Tc-glutathione etc. All of these Tcs proved to be concentrated in some tumor and/or inflammatory sites. Moreover, other complexes for imaging inflammation, e.g. human immunoglobulin Gb and 99Tcm "HIgG-99Tcm" is an interesting serendipity drug developed from the reduction of disulphides (-S-S-) under very mild conditions to produce free –SH groups. The efficacy of the formed labeled chemotactic complexes act as substrate(s) for imaging infection *via* binding to receptors whereas WBC (leucocytes) are in high concentration at the location of infection [8, 10].

#### *7.1.1 Tcm-Ciprofloxacin*

HPLC analysis showed that the efficacy of the radiolabeled Tcm-Ciprofloxacin is over 95%. Meanwhile, *In vivo* bioavailability studies using mice showed that "Tcm-CIP is quickly bioavailable and distributed upon intravenous administration with a major renal clearance. In the infection inflammatory model on mice induced by turpentine oil, *S. aureus*, and *E. coli*, the radiopharmaceutical preparation was successful in localization of bacteria in the inflamed site [11].

#### **7.2 Neurology and psychiatry**

Molecular biology plays a crucial role in identifying many receptors and subtype receptors for neurotransmitters. Subsequently, this encourages radiopharmaceutical industry to conduct neuroreceptors brain imaging as is one of the major application of the radiopharmaceutical research [7].

#### **7.3 Renal tubular function agents**

A true replacement to hippuran-123I has been a challenging task in the development of technetium complexes, as no Tc compound is completely extracted and secreted into urine. It has, however, been possible to develop compounds which are handled by the renal tubules and actively secreted into urine. Structural feature requirements for recognition by renal tubules and for delivery by serum protein bound transport propounded way back by Despopoulos, [-C(=O)-NH-CH2-COOH], have been sought in the technetium complexes to achieve some degree of success. For most clinical purposes, a renogram agent based on renal tubular handling would be very much more useful, apart from being superior to purely GFR based agent such as 99Tcm -DTP A, and hence the intense research efforts. Tc-MAG3 complex contains the structure referred to above, while Tc-EC has a structural mimic, 3 oxygen atoms at 3–4 A0 to one another in Tc(=O)-NH-CH2-COOH, cf. -C(=O)-NH-CH2-COOH [9]. Both Tc-MAG3 and Tc-EC show less excretion than hippuran, but Tc-EC has relatively superior features. The room temperature formulation recipe of Tc-EC is another practical advantage. The early apprehensions of differences in the purity of kit formulated and

*Radiopharmaceuticals: On-Going Research for Better Diagnosis, Therapy, Environmental… DOI: http://dx.doi.org/10.5772/intechopen.99204*

chromatographically purified product were removed with refinements in kit formulation procedures. However, due to inherent nature of possible trace impurities in MAGS synthesis as well as different types of TcMAG3 complexes feasible, interference from hepatobiliary involvement during renography studies has not been ruled out. One study is in fact devoted to the anomalies in Tc-MAG3 behavior, Modifications to MAG3 ligands to overcome the drawbacks have been sought, replacing glycine by another amino acid, introduction of chiral center to influence the stereochemical role etc.; some superior results have been achieved, like 99Tcm -D-MAGAG. Tc-L, L-EC requires to be prepared at highly alkaline pH of 11–12 and it is consequently difficult to present in a reliable single component lyophilized kit form, though a commercial kit has been cited in literature. Detailed stringent protocol for kit formulation has been suggested. A multi-component kit recipe would be generally necessary, but advantage of ease of transchelation (using GHA) based kit has also been reported. As discussed earlier, the development of Tc-EC for renal tubular function, is an outcome based on the excretory pattern of Tc-ECD and the study of its metabolite(s) [12]. The attempts to utilize cysteine, cystine and analogues for complexing technetium for obtaining renal agents had shown mixed findings, but the same group from India has recently demonstrated a new product for renal tubular function imaging. 99Tcm complex of dimethyl ester of DTPA denoted as Tc-DMDTPA, has shown promising results including in human volunteers. Analogous to Tc-DTPA, the Tc-DMDTPA complex is anionic, but has predictably less (−50%) electrophoretic mobility. Ease of reliable, stable, single component lyophilized kit formulation, room temperature preparation of Tc-DMDTPA in high yield, purity and stability and similarity in biological behavior to hippuran- l j lI and Tc-MAG3 in both normal and probenecid (renal tubular transport inhibitor) treated mice are the salient advantages reported. A cationic pathway renal tubular agent has also been reported from UK involving the complex of 1,2-diaminocyclohexane (DACH). The product, [Tc(V)02(DACH)2]", is formulated using stannous tartrate reduction of pertechnetate and has shown utility for eliciting renal tubular function, when anionic pathway is not freely accessible due to high concentrations of circulating anions, like during chemotherapy [9, 12].

#### **8. Research and Development**

#### **8.1 Milestones and concepts in the evolution of new products**

In the genesis of the growth of 99Tcm compounds, the introduction of DTPA chelate of technetium, use of stannous tin for reduction of Tc (VTT) in pertechnetate and lyophilization of premixed stannous tin - ligand formulation would merit the first mention despite the passage of time. Suitable variation(s) in the functional groups on the ligand backbone to influence the pharmaco-kinetic behavior of the resultant technetium complexes, while retaining the same chelating environment for technetium, was a major development. This eventually led to introduction of the most preferred hepatobiliary tracer, 99Tcm-mebrofenin [2]. Such systematic investigations of structure - activity distribution relation (SADR) provided a fresh approach for the development of many other new products. The concept of bifunctional nature of ligands was also propounded after this work, for in LID As, IDA groups participate in complexing technetium, while the phenylcarbamoyl moiety bestows some of the required biological features. Although in the present sense of the term BCA, this may not be strictly correct, the way was paved for a new approach to develop "Tcm compounds [13].
